Spontaneous voltage oscillations in striatal projection neurons in a rat corticostriatal slice

doi:10.1113/jphysiol.2003.050799

Spontaneous voltage oscillations in striatal projection neurons in a rat corticostriatal slice

R. Vergara, C. Rick, S. Hernández-López, J. A. Laville, J. N. Guzman, E. Galarraga, D. J. Surmeier* and J. Bargas

Department of Biophysics, Instituto de Fisiología Celular UNAM, Mexico City 04510, Mexico and *Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago 60611, USA

ABSTRACT

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Abstract
Introduction
Methods
Results
Discussion
References

In a rat corticostriatal slice, brief, suprathreshold, repetitive cortical stimulation evoked long-lasting plateau potentials in neostriatal neurons. Plateau potentials were often followed by spontaneous voltage transitions between two preferred membrane potentials. While the induction of plateau potentials was disrupted by non-NMDA and NMDA glutamate receptor antagonists, the maintenance of spontaneous voltage transitions was only blocked by NMDA receptor and L-type Ca²⁺ channel antagonists. The frequency and duration of depolarized events, resembling up-states described in vivo, were increased by NMDA and L-type Ca²⁺ channel agonists as well as by GABA_A receptor and K⁺ channel antagonists. NMDA created a region of negative slope conductance and a positive slope crossing indicative of membrane bistability in the current-voltage relationship. NMDA-induced bistability was partially blocked by L-type Ca²⁺ channel antagonists. Although evoked by synaptic stimulation, plateau potentials and voltage oscillations could not be evoked by somatic current injection - suggesting a dendritic origin. These data show that NMDA and L-type Ca²⁺ conductances of spiny neurons are capable of rendering them bistable. This may help to support prolonged depolarizations and voltage oscillations under certain conditions.

(Resubmitted 4 July 2003; accepted after revision 4 September 2003; first published online 5 September 2003)
Corresponding author J. Bargas: Insituto de Fisiología Celular UNAM, PO Box 70-253, Mexico City DF 04510, Mexico. Email: jbargas{at}ifisiol.unam.mx

INTRODUCTION

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Abstract
Introduction
Methods
Results
Discussion
References

The striatum is a component of the basal ganglia circuitry controlling movement, associative learning and procedural memory (e.g. Beiser & Houk, 1998). Its output neurons are the medium spiny neurons (Wilson, 1993). In vivo, these neurons move between hyperpolarized 'down-states' and depolarized 'up-states' in response to cortical excitatory synaptic input (Wilson, 1993; Stern et al. 1997). We wanted to know whether similar voltage fluctuations could be induced in vitro.

In a variety of cell types, the generation of stable depolarized states depends upon a combination of synaptic inputs and intrinsic conductances (e.g. Lee & Heckman, 1998a; Russo & Hounsgaard, 1999). Persistent or slowly inactivating Ca²⁺ currents (Seamans et al. 1997; Carlin et al. 2000; Perrier & Hounsgaard, 2000) and slowly inactivating sodium currents (Schwindt & Crill, 1998; Hsiao et al. 1998; Larkum et al. 2001) figure prominently in the maintenance of depolarized plateau potentials in many neurons. These currents create a region of negative slope conductance and a second stable point in the current-voltage relationship (Booth et al. 1997; Kiehn & Eken, 1998; Hsiao et al. 1998; Lee & Heckman, 1998b; Schiller & Schiller, 2001; Svirskis et al. 2001). In this situation, neurons become bistable, allowing transient depolarizing synaptic inputs to produce prolonged depolarizations and sustained periods of spiking. Sustained periods of spiking are the cellular correlate of working memory (Romo et al. 1999; Compte et al. 2000; Egorov et al. 2002) and the neostriatum with prefrontal and motor cortices are posited as the basic circuit for procedural memory (Beiser & Houk, 1998).

Often, bistability emerges in response to agonists or neuromodulators that enhance NMDA and inward currents (Guertin & Hounsgaard, 1998; Perrier & Hounsgaard, 2000; Wang & O'Donnell, 2001; Schiller & Schiller, 2001; Egorov et al. 2002). One of these inward currents is carried by L-type Ca²⁺ channels (Hounsgaard & Kiehn, 1989) and L-type Ca²⁺ channels are known to be modulated by dopamine in neostriatal neurons (Hernandez-Lopez et al. 1997, 2000). Two types of these channels have been located in the somato-dendritic membrane of many neurons: Cav1.2 and Cav1.3 (Westenbroek et al. 1998; Xu & Lipscombe, 2001). Cav1.3 L-type channels may be particularly important in this regard as they activate at subthreshold membrane potentials (Koschak et al. 2001; Xu & Lipscombe, 2001). Striatal medium spiny neurons express mRNA for both subtypes and have a prominent L-type current at subthreshold membrane potentials (Bargas et al. 1994; Olson et al. 2001). The contribution of this current to shape the normal firing pattern (Galarraga et al. 1989, 1994; Perez-Garci et al. 2003) and the synaptic responses (Galarraga et al. 1997; Akopian & Walsh, 2002) are well-established. Enhancement or block of these currents with dihydropyridine L-type channel agonists and antagonists facilitates or blocks, respectively, plateau potentials or their underlying currents in spiny neurons (Galarraga et al. 1997; Hernandez-Lopez et al. 1997, 2000; Cepeda et al. 1998; Akopian & Walsh, 2002).

Therefore, we asked whether synaptic activation could be elicited in conditions that were permissive for the participation of these inward currents. In addition, we wanted to explore whether the participation of these inward currents would favour the generation of spontaneous voltage oscillations. In slices that preserve some measure of corticostriatal connectivity, it was seen that transient stimulation of the cortex is capable of inducing long-lasting plateau potentials in spiny neostriatal neurons (Bargas et al. 1991; Galarraga et al. 1997; Schlosser et al. 1999). Similar plateau potentials have been observed in vivo (Herrling et al. 1983; Wilson et al. 1983). It was also observed that, upon repetitive stimulation, plateau potentials were often followed by spontaneous fluctuations between two different membrane potentials. The probability of these transitions was strongly modulated by the enhancement of inward currents known to underlie bistability in several cell types - namely L-type Ca²⁺ and NMDA currents.

METHODS

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Abstract
Introduction
Methods
Results
Discussion
References

Preparation

Young Wistar rats (18 days old) were anaesthetized with ether and the brain was quickly removed into ice-cold saline (4 °C) containing (mM): 123 NaCl, 3 KCl, 1 MgCl₂, 1 CaCl₂, 25 NaHCO₃ and 11 glucose (25 °C; pH 7.4 with NaOH, 298 mosmol l^-1 with glucose; saturated with 95 % CO₂/5 % O₂). Parasagittal neostriatal slices (300 µm thick) were cut in 4 °C saline using a vibratome. Slices were then transferred to saline at room temperature (21-25 °C) where they remained for at least an hour before recording. All procedures conformed with the Animals Scientific Procedures Committee guidelines of the Instituto de Fisiología Celular and the Northwestern University. Individual slices were transferred to a plexiglass recording chamber and superfused with the above saline (3-6 ml min^-1) at room temperature (21-25 °C). The cationic concentration of this saline favours the appearance of up-states in vitro (Sanchez-Vives & McCormick, 2000).

Whole-cell recordings

Standard whole-cell techniques using an Axoclamp 2B amplifier were employed. Micropipettes were pulled from borosilicate glass and fire polished (2-7 M $Omega$ ). The internal solution contained (mM): 115 KH₂PO₄, 2 MgCl₂, 10 Hepes, 0.5 EGTA, 2 Na₂ATP and 0.2 Na₃GTP (pH 7.2, 275 mosmol l^-1). Neurons roughly 100-150 µm below the surface were chosen for recording. Preliminary experiments used biocytin injections made focally into extracellular space in slice preparations maintained in vitro in the recording chamber (6-8 h). In conditions similar to those used for electrophysiological recordings, cortical injections of biocytin revealed the trajectory of several corticostriatal fibres crossing through the corpus callosum in the slice. Our recordings were carried out in those areas of the dorsal striatum that most frequently receive an abundance of those fibres. A commonly used arrangement of recording and stimulating electrodes is indicated in Fig. 1A. The stimulation of cortical white matter or cortical sensory motor areas was performed with concentric bipolar electrodes (12 µm at the tip). Stimuli were controlled through the computer interface (see below) with a LabView program (National Instruments, Austin, TX, USA). Isolation units between the computer and the stimulating electrodes were used to change stimulus parameters during the experiment. Neurons with negative resting membrane potentials (<-70 mV) and input impedance about 200 M $Omega$ were chosen for further study. Voltage steps or voltage ramp commands were used to perform current-voltage relationships (I-V plots). Synaptic potentials and orthodromic responses were recorded in control saline and during the superfusion with N-methyl-D-aspartate (NMDA: 5-25 µM). All recordings were filtered at 1-3 KHz and digitized with an Instrutech digitizer (Instrutech Corp., Long Island, NY, USA) and an AT-MIO-16E10 (National Instruments) with a DAQ board (NI-DAQ) (National Instruments) in a PC. The Instrutech digitizer was connected to a tape recorder for off-line analysis, while the NI-DAQ board was used to save data directly to a computer. On-line data acquisition used custom LabView programs.

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Figure 1. Cortical stimulation evoked long-lasting plateau potentials with repetitive firing in medium spiny neurons
A, scheme of a brain slice showing the connection stimulated. The stimulating electrode was placed in the cortical grey or white matter (pyramidal cell scheme), and the recording electrode on the dorsal neostriatum (neostriatal cell scheme). B, orthodromic response of a spiny neostriatal neuron to single subthreshold and suprathreshold stimulus in the cortex. Notice plateau potential with repetitive discharge after suprathreshold stimulus. C, a three times threshold cortical stimulus now evokes a plateau potential followed by several membrane potential oscillations, some of which exhibit the firing of action potentials. This behaviour is more commonly elicited with a stimulus train (see Fig. 4B). The time scale is different in B and C. D, a stimulus train can also evoke an arrhythmic sequence of voltage oscillations in pyramidal cells (sensorimotor cortex, layer 5). E, firing of a neostriatal neuron after a intracellular current injection at the soma (current stimulus not shown). F, firing of a neostriatal neuron during an spontaneous depolarization or 'up-state'. Action potentials are clipped due to digitization procedures in E and F.

Digitized data were imported for analysis and graphing with commercial software (Igor Pro, Wavemetrics, Lake Oswego, OR, USA). Non-parametric, distribution-free statistical procedures (Systat, SPSS, Chicago, IL, USA) were used to determine the significance of differences in group measures.

Drugs used were: 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline disodium salt (CNQX), D-(-)-2-amino-5-phosphonovaleric acid (AP5), N-methyl-D-aspartate (NMDA), nicardipine, nitrendipine, BayK 8644, tetraethylammonium (TEA), picrotoxin and bicuculline (Sigma-Aldrich-RBI, St Louis, MO, USA).

RESULTS

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Abstract
Introduction
Methods
Results
Discussion
References

Cortical stimulation is capable of evoking plateau potentials and voltage oscillations in medium spiny neurons

In a parasagittal slice (Fig. 1A), stimulation of the cortical grey matter was capable of evoking long-lasting depolarizations with repetitive action potentials in nearby medium spiny neurons (Bargas et al. 1991). As shown in Fig. 1B, subthreshold EPSPs decayed rapidly back to baseline. Increasing the stimulus intensity (more than two times threshold) resulted in the generation of a long-lasting plateau potential with repetitive firing (Fig. 1B). The amplitude of EPSPs evoking plateaus was only marginally larger (as seen with a somatic electrode) than that of near threshold EPSPs. Plateau potentials lasting 200-800 ms in response to single or paired cortical stimulus were seen in about half of the trials (cf. Fig. 7A). Activation of plateau potentials depended on non-NMDA receptor-mediated synaptic transmission, as cortical stimulation was without effect in the presence of CNQX (10 µM, n = 25). When the strength of cortical stimulation was increased above three times threshold, the initial plateau potential could be followed by oscillations of the membrane potential (Fig. 1C) that lasted several seconds without any further stimulus. Some of these oscillations exhibited firing. As shown below, this type of behaviour was more commonly elicited with a stimulus train (Fig. 4B and Fig. 5C) or a pair of suprathreshold stimulus (Fig. 2 and Fig. 3). Pyramidal cells in the sensorimotor cortex can also respond with a sequence of voltage oscillations after a stimulus train (Fig. 1D, 30 Hz for 500 ms, upward deflections signalled by the arrow are the stimulation artifacts) (Shu et al. 2003). In contrast to tonic firing encountered in spiny cells after intracellular current injections at the soma (Fig. 1E), the firing during the depolarizing transitions, or up-states, was irregular in nature (Fig. 1F; cf. Cossart et al. 2003). To our knowledge, this is the first report showing that membrane potential oscillations can be evoked in a neostriatal slice preparation. Synaptic activation from the cortex generates plateau potentials in about half of neostriatal cells (n = 40/80), and in about 10 % of the cells exhibiting plateau potentials voltage oscillations could ensue. In addition, voltage oscillations could also be recorded in some cells in the absence of stimulus (e.g. Fig. 5). The appearance of voltage oscillations after a cortical stimulus suggested that this type of response was physiological, although rather uncommon in the slice. Some of the following experiments attempted to find conditions that further facilitate the appearance of voltage oscillations in spiny neurons recorded in vitro.

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Figure 2. Evoked oscillation of the membrane potential after repetitive cortical stimulation
A, a pair of cortical stimuli (arrow) produces a plateau potential similar to that depicted in Fig. 1 (cf. time scale). B, repetition of the stimulus at 0.1 Hz produced a late subthreshold depolarization after the plateau potential produced by the third stimulus. C, continuous repetition of the same stimulus induced a suprathreshold late depolarization after the plateau potential evoked by the sixth stimulus. D, a continuous oscillation of the membrane potential followed this later plateau (see change in time scale, action potentials are clipped or incomplete due to digitization) without any further cortical stimulus. Several cells exhibited a tendency to slowly depolarize but continued to exhibit voltage oscillations for several minutes without overt cortical stimulation. E, an all point histogram of the membrane potential is shown for this cell. Notice Gaussian distributions around two different membrane potential values. F, a scatter plot for two-state membrane potential is shown for a sample of cells. This experiment was performed in the absence of NMDA. However, in other cells, NMDA greatly facilitated the appearance of membrane potential oscillations after the initial, evoked, plateau potential.

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Figure 3. Plateau potentials are easily evoked after paired pulse stimulation
A, from top to bottom, the time interval between a pair of cortical stimuli was reduced without changing the stimulus strength. Notice a prolonged depolarization capable of sustaining repetitive firing after the briefer interval. B, the responses to a pair of subthreshold stimuli are shown. They were recorded at two different holding potentials. Paired-pulse facilitation is shown at -60 mV, and depression at -70 mV (top). However, if stimulus strength was increased, a prolonged depolarization could be elicited at -70 mV (bottom). This was never obtained by depolarizing the soma with current injections. C, a cell was hyperpolarized to -92 mV (top) while having voltage oscillations, as in Fig. 2D. Oscillations were reduced in both duration and amplitude to finally stop after this manoeuvre. An all point histogram (bottom) revealed bimodality of the membrane potential at -70 mV, but only a single peak at -92 mV.

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Figure 4. NMDA facilitates plateau potentials and membrane potential oscillations
A, a pair of synaptic responses was evoked with cortex stimulation. Only the second EPSP reached threshold (control). Addition of NMDA (25 µM) increased the duration of the second response and produced a plateau potential. Thus, NMDA mimicked an increase in stimulus strength (+NMDA). B, a train of orthodromic subthreshold stimuli were given at the cortex (arrow signals upward deflections of stimulus artifacts). The response was subthreshold to produce any plateau or oscillatory response (control). Superfusion with NMDA (25 µM) without a cortical stimulus did not produce oscillatory responses in most cases (+NMDA). However, the combined administration of a cortical stimulus and NMDA evoked membrane potential oscillations after a variable latency (two continuous traces at bottom). C, a 2 s ramp was given at the soma and the whole current response plotted against this voltage command. Control response shows firing of unclamped action currents but no crossings of the zero current axis. Addition of NMDA (20 µM) facilitated a negative slope conductance region, and a double crossing of the zero current axis, indicative of bistability (+NMDA). D, reduction of the electrotonic length with Ba²⁺, shifted the first crossing of the zero-current axis and the negative slope conductance region to the left in the voltage axis. This suggests that the origin of bistability is located on the dendrites. The graph also shows the inward rectifier block by Ba²⁺.

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Figure 5. AP5 blocks membrane potential oscillations
A, representative sweeps of spontaneous (in the absence of cortical stimulus or NMDA) membrane potential oscillations recorded in a neostriatal neuron (control). Action potentials are clipped or incomplete due to digitizing procedures. B, addition of AP5 (50 µM) in the bath saline blocked the membrane potential oscillations (+AP5). C, membrane potential oscillations could be restored after cortical stimulation and addition of NMDA (10 µM) during AP5 wash-out (AP5 wash-out + NMDA). D, AP5 could block voltage oscillations induced by cortical stimulation and NMDA in a sample of cells as this one (+AP5 traces at bottom).

In many occasions, slow repetition (0.1 Hz) of a cortical stimulus that initially only evoked a plateau potential (two to three times threshold) frequently resulted in the emergence of nominally autonomous oscillations that persisted for many minutes. An example is shown in Fig. 2. Here, the initial cortical simulation elicited a plateau potential with repetitive firing (Fig. 2A). The third stimulation elicited not only the initial response but also a later depolarization that was sub-threshold (Fig. 2B). The sixth stimulation elicited a more prolonged initial plateau with discharge and a later plateau also with discharge that lasted over 1 s (Fig. 2C). This second plateau was followed by membrane potential oscillations that, once initiated, continued without overt cortical stimulation (Fig. 2D) for several minutes. During these nominally autonomous, aperiodic oscillations, the membrane potential distribution was distinctly bimodal (Fig. 2E) (Wilson & Kawaguchi, 1996; Stern et al. 1997). However, the membrane potential of the nominal down-state mode varied considerably in these in vitro preparations (-80 to -65 mV), in contrast with the in vivo situation. Nonetheless, the depolarized mode was always near spike threshold (-55 to -50 mV). A scatter plot of the two modes in a sample of neurons (n = 7) is shown in Fig. 2F.

Although synaptic stimulation evoked plateau potentials that outlasted stimulus duration (Fig. 1 and Fig. 2) and that could be followed by membrane potential oscillations, depolarizing current injections at the soma were unable to elicit this behaviour (Fig. 1E). Somatic current injection could induce plateau potentials only from depolarized holding potentials (>-60 mV; not shown but see Hernandez-Lopez et al. 1997, 2000). This is in contrast with the situation found in other types of neuron (Hsiao et al. 1998; Lee & Heckman, 1998a; Kiehn & Eken, 1998; Russo & Hounsgaard, 1999; Egorov et al. 2002). These observations are consistent with the proposition that the somatic membrane of medium spiny neurons is not bistable (Wilson & Kawaguchi, 1996; Stern et al. 1997). However, since most synaptic inputs are located in the dendrites (Wilson, 1993), it is possible that it is the dendritic membrane, not the somatic, that expresses the ion channel machinery capable of producing the plateau potentials observed after cortical stimulation. If this were the case, summation of synaptic inputs, should efficiently activate intrinsic inward conductances in the dendrites due to their temporal profile (Larkum et al. 2001). Thus, a pair of synaptic inputs should be particularly effective in evoking plateau potentials. In agreement with this view, a pair of near-threshold stimuli delivered in rapid succession evoked a plateau potential when the inter-stimulus interval was less than 50 ms (Fig. 3A). On the other hand, membrane depolarization to -60 mV during a pair of stimuli, enhanced the second synaptic response (Fig. 3B, top) (see Galarraga et al. 1997; Akopian & Walsh, 2002), whereas hyperpolarization to -70 mV led to paired pulse depression of the same responses. At -70 mV, the generation of prolonged depolarizations needed stronger stimulus strength (Fig. 3B, bottom). Finally, Fig. 3C shows that once membrane potential oscillations were activated by cortical stimulation (as in Fig. 2D), a strong hyperpolarization (ca. -90 mV) disrupted the generation of the oscillations. However, notice that oscillations continued during a brief time although their amplitude and duration were reduced. Hyperpolarization led to a positively skewed membrane potential distribution, and the elimination of the second 'preferred' state and bimodality (Fig. 3C, bottom). Taken together (Figs 1-3), these experiments suggest that synaptic activation induce the operation of voltage-dependent conductances (Bargas et al. 1991; Galarraga et al. 1997; Cepeda et al. 1998; Akopian & Walsh, 2002).

NMDA receptor activation promotes cortically evoked plateau potentials

Previous studies have implicated NMDA receptors in the potentiation of synaptic and oscillatory responses in medium spiny neurons, particularly at depolarized membrane potentials (Herrling et al. 1983; Cherubini et al. 1988; Galarraga et al. 1997; Cepeda et al. 1998; Akopian & Walsh, 2002). By potentiating $alpha$ -amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate (AMPA/KA) receptor mediated synaptic responses, NMDA receptors may contribute to generate dendritic plateau potentials. If NMDA receptors in the dendritic region depolarized by the synaptic input are not saturated, the addition of NMDA to the bath should enhance the synaptic response (Schiller & Schiller, 2001). To explore this possibility, the ability of exogenous NMDA to potentiate near threshold synaptic responses was examined. Figure 4A (top) shows records of a neuron in which the stimulus strength of a pair of cortical stimuli was adjusted so that the first EPSP was subthreshold and the second EPSP evoked a single spike to decay rapidly back to the resting membrane potential. This response was completely abolished by the AMPA receptor antagonist CNQX (10 µM; n = 25, not shown). When NMDA (25 µM) was added to the bath and the stimulus protocol repeated, the response became more prolonged, ostensibly mimicking the effect of increasing stimulus strength. This suggests that NMDA was acting to potentiate only the synaptic responses that were strong enough to produce local relief from Mg²⁺ blockade. Further, this result suggests that synaptic suprathreshold stimulation may be capable of activating NMDA synaptic receptors, and, in this way, elicit plateau potentials.

Next, the impact of NMDA on the generation of membrane potential oscillations was examined. Bath application of NMDA (10-25 µM) enhanced the ability of cortical stimulation to induce voltage oscillations in medium spiny neurons. An example is shown in Fig. 4B. In the absence of NMDA, a brief subthreshold train of stimuli (30 Hz for 500 ms, upward deflections signalled by the arrow are the simulation artifacts) from the cortex evoked only small synaptic depolarizations in the recorded neuron (Fig. 4B, control). This stimulation was clearly subthreshold to produce plateau potentials. On the other hand, NMDA alone (25 µM) did not induce voltage oscillations or plateaus (Fig. 4B, +NMDA). However, the same cortical stimulus in the presence of NMDA was able to induce oscillations in the membrane potential (Fig. 4B two continuous traces at bottom). Oscillations appeared after a latency of seconds but then persisted for minutes without additional cortical stimulation. Similar results were obtained in 30 out of 50 neurons. In 5 out of 50 neurons, NMDA induced voltage oscillations without overt cortical stimulation. In four neurons suprathreshold cortical stimulation without NMDA was enough to elicit both plateau potentials and voltage oscillations (vg. Fig. 1C). This is in contrast to the in vivo situation in which NMDA alone is capable of eliciting voltage oscillations in most instances (Herrling et al. 1983), suggesting that cortical synaptic activity onto spiny cells is much lower in vitro. In three other neurons, spontaneous voltage oscillations were seen without the addition of NMDA or cortical stimulation (see below).

The emergence of voltage oscillations in the presence of NMDA may be linked to alterations in the current-voltage relationship of medium spiny neurons in the dendritic regions where synaptic NMDA receptors are present (Schiller & Schiller, 2001). In many neurons, NMDA induces a region of negative slope conductance and a second crossing, with positive slope, of the zero-current axis by the current-voltage relationship. This is the landmark of membrane potential bistability (Booth et al. 1997; Kiehn & Eken, 1998; Schiller & Schiller, 2001; Svirskis et al. 2001). To determine whether NMDA can act in this way in medium spiny neurons, neurons were subjected to somatic voltage clamp and ramped from -80 to 0 mV in 2 s in the presence and absence of NMDA. A typical result is shown in Fig. 4C. In the absence of NMDA at this ramp speed, there was only a small region in which the current-voltage relationship (I-V plot) had a negative slope as seen from the soma (cf. I-V plot hysteresis in Galarraga et al. 1994). There was not a second stable point evident from the soma. However, after the addition of NMDA (10-25 µM), a negative slope region was frequently present and a second, positive slope crossing of the zero-current axis was apparent (Fig. 4C +NMDA; n = 9/10; Schiller & Schiller, 2001). Similar results were obtained with voltage steps (n = 5; see Fig. 7C). However, the NMDA-induced negative slope region was at much more depolarized potentials than one would predict on the basis of the current clamp recordings where the up-state is near -50 mV (Booth et al. 1997). A potential explanation for the differences between these two results is that the bistable region induced by NMDA was dendritic; therefore, it was electrotonically remote from the somatic electrode. Certainly, the vast majority of glutamatergic synapses - and presumably NMDA receptors - are dendritic in medium spiny neurons and hundreds of microns from the soma (Wilson, 1993). If this were relevant, shortening the electrotonic structure of medium spiny neurons should bring these synaptic regions closer to the soma and reduce the differences (Reyes et al. 1998). Besides leak channels, the principal channels governing the electrotonic structure of medium spiny neurons at hyperpolarized membrane potentials are members of the Ba²⁺-sensitive Kir₂ family (Galarraga et al. 1994; Mermelstein et al. 1998; Reyes et al. 1998). In agreement with this hypothesis, the addition of Ba²⁺ (200 µM) to the bath dramatically shifted the negative slope crossing of the zero current axis (modal shift = -22 mV, n = 4). In contrast, the second positive slope crossing was not significantly shifted by the addition of Ba²⁺ in most of these neurons, as for the neuron illustrated in Fig. 4D (modal shift = -2 mV, n = 4); as one might predict based upon the ability of depolarization activated K⁺ channels to limit depolarization and lengthen the electrotonic length of the dendrites in these cells (Nisenbaum et al. 1996; Bargas et al. 1999). To conclude, the activation of NMDA receptors can induce changes in the I-V plot of medium spiny neurons that allow the establishment of membrane potential bistability. These changes most probably occur at the dendritic arbor. But, do these changes take place during spontaneous activity or in response to cortical stimulation?

When NMDA is present in the extracellular space it can bind to its receptors, which only need a brief depolarization to induce sustained periods of activity. In the presence of chaotic synaptic inputs, this may lead to voltage oscillations of the membrane potential (Schiller & Schiller, 2001). Figure 5 illustrates recordings from a neuron which exhibited spontaneous voltage oscillations a few seconds after obtaining the whole-cell configuration, that is, without cortical stimulation or exogenous NMDA (control). Addition of the NMDA receptor antagonist, AP5 (50 µM), to the bath saline abolished the voltage oscillations (Fig. 5B, +AP5), suggesting that this preparation had enough endogenous glutamate capable of activating NMDA receptors. However, wash-out of AP5 was not enough to restore the oscillations. Nonetheless, if 10 µM NMDA was added to the bath saline, together with cortical stimulation (arrow, 30 Hz for 500 ms), the oscillations could be re-established (Fig. 5C). AP5 blocked all voltage oscillations in two cells that exhibited this behaviour spontaneously and in 8 out of 10 cells in which oscillations were produced by cortical stimulation and NMDA (10-25 µM; Fig. 5D). In two cells, short lasting oscillations could still be induced after AP5 (Cossart et al. 2003). It is concluded that, as in many other neuron types, NMDA receptors are important in producing bistability and spontaneous or evoked voltage oscillations (Fig. 4 and Fig. 5). The experiments suggest that these oscillations represent a physiological phenomenon and that exogenous NMDA only facilitates it; perhaps, by replacing the loss of convergent synaptic inputs. Since NMDA receptors are important for the synaptic response of these neurons (Cherubini et al. 1988), its activation may possible help to the generation of plateau potentials and the subsequent voltage oscillations (Herrling et al. 1983). This activity can be triggered by endogenous or exogenous agonists.

Finally, the addition of the K⁺ channel blocker TEA (1 mM) (in the presence of 10-25 µM NMDA) increased the number of neurons in which cortical stimulation evoked similar voltage oscillations (not shown; see Nisenbaum et al. 1996).

CNQX did not alter membrane potential oscillations once they start

Surprisingly, and despite of the fact that the AMPA receptor antagonist CNQX blocked the plateau potential evoked by cortical stimulation, Fig. 6 illustrates that once the membrane potential oscillations began (Fig. 6A), CNQX (10 µM) failed to terminate them (Fig. 6B). The duration of up-states was 1.1 ± 0.11 s in the control and 1.2 ± 0.12 s in the presence of CNQX (NS; n = 7; see box plots in Fig. 6C). Neither frequency nor down-state membrane potential changed significantly after CNQX. These results suggest that, in the present conditions, AMPA transmission is required to induce the initial cortically evoked plateau potentials, but not necessary for the maintenance of the subsequent voltage oscillations. It is then concluded that other synaptic components are capable of maintaining the oscillations (e.g. Szabadics et al. 2001; Cossart et al. 2003; Kilb & Luhmannn, 2003).

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Figure 6. CNQX does not block membrane potential oscillations
A, membrane potential oscillations were induced by repetitive cortical stimulation plus NMDA (10 µM). B, once induced, membrane potential oscillations did not change in frequency or duration after the addition of CNQX (10 µM). C, box plots illustrate distributions of up-state duration before and during CNQX in a sample of neurons (n = 7).

L-type Ca²⁺ channels promote plateau potential generation

As mentioned above, in other neuron types L-type Ca²⁺ channel currents are major regulators of bistability. Previous work has shown that L-type Ca²⁺ channels in striatal medium spiny neurons are essential for the expression of their characteristic tonic firing pattern, input-frequency function and firing threshold (Perez-Garci et al. 2003). They are also necessary to promote the generation of plateau potentials from relatively depolarized holding potentials if elicited from the soma (-60 to -55 mV) (Hernandez-Lopez et al. 1997, 2000). Finally, L-type Ca²⁺ currents are known to potentiate the synaptic activation of NMDA receptors in medium spiny neurons (Galarraga et al. 1997; Cepeda et al. 1998; Akopian & Walsh, 2002). But do L-type Ca²⁺ currents play a role in the generation of synaptically evoked plateau potentials? Do they participate in the generation of membrane potential oscillations in response to cortical stimulation? To help answer these questions, the ability of L-type Ca²⁺ channel antagonists to suppress evoked plateau potentials was examined. Figure 7A (top) shows a prolonged plateau potential evoked in a medium spiny neuron by paired suprathreshold cortical stimulation (Kiehn & Eken, 1998). The application of the L-type Ca²⁺ channel antagonist, nitrendipine (5 µM) (Fig. 7A +nitrendipine), reduced the plateau potential in this and other cells tested (control plateau duration 750 ± 112 ms, n = 6 vs. 208 ± 98 ms, n = 4; P < 0.01; Mann-Whitney U test). Similar results were obtained with the L-type channel antagonists nimodipine (5 µM, n = 3) and nicardipine (5 µM, n = 2). Addition of the NMDA receptor antagonist, AP5 (50 µM), in the presence of the L-type channel antagonists, blocked the remaining depolarization and revealed the underlying EPSPs (Fig. 7A +AP5). A variance in the amplitude of the first spikes of the train on top of the plateau potential was noticed. Although to a lesser degree, this is also seen in Figs 1B, 2A-C and 3A (bottom). Up-states commonly exhibited variations in spike amplitude. This has been reported before (Bargas et al. 1991; Hsiao et al. 1998) and it has been explained by depolarizations strong enough to propagate to the spike triggering zone (Larkum et al. 2001), thus partially inactivating the spikes as seen from the somatic electrode.

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Figure 7. L-type Ca²⁺ channels participate in the generation of synaptically evoked plateau potentials and membrane potential oscillations
A, a pair of suprathreshold cortical stimuli evoked a long-lasting plateau potential in a spiny cell (control). Notice sustained firing. Addition of the L-type Ca²⁺ channel antagonist, nitrendipine (5 µM), blocked most of the plateau potential (+nitrendipine). The subsequent addition of the NMDA receptor antagonist, AP5 (50 µM), blocked the remaining slow depolarization disclosing the underlying EPSPs (+AP5). B, membrane potential oscillations were evoked with cortical stimulation and NMDA (10 µM)(control). Addition of the L-type Ca²⁺ channel antagonist, nicardipine (5 µM), blocked the oscillations and made cortical stimulation ineffective for evoking them. C, superimposed current-voltage (I-V) plots from a medium spiny cell (control). Addition of NMDA (20 µM) induces a negative slope conductance region and bistability. A subsequent addition of nitrendipine (5 µM) to the bath saline abolished the negative slope conductance region induced by NMDA.

Next, membrane potential oscillations were induced by cortical stimulation and NMDA (10 µM) (Fig. 7B). In this situation, nicardipine (5 µM) not only stopped the ongoing oscillations but also prevented subsequent cortical stimulation from evoking oscillations (Fig. 7B). Similar results were obtained in four other neurons. In addition, I-V plots built with somatic voltage commands revealed that L-type Ca²⁺ channel blockade (nitrendipine, 5 µM) eliminated the negative slope conductance region created by the addition of NMDA (Fig. 7C, n = 4). Thus, despite being induced by NMDA receptor activation, the negative slope conductance region is in part due to the activation of intrinsic inward currents (Hsiao et al. 1998). These results argue that L-type Ca²⁺ channels work together with NMDA receptors to promote bistability in medium spiny neurons (Galarraga et al. 1997).

If L-type channels are involved in plateau potential generation, then facilitating channel opening should enhance the response to cortical stimulation. Two types of experiments were performed to test this hypothesis. First, cortically evoked EPSPs were used to generate plateau potentials in the presence of NMDA (20 µM) and TEA (1 mM). As predicted, the addition of BayK 8644 (5 µM) significantly increased the duration of the plateau (control duration: 750 ± 112 ms; BayK 8644: 1344 ± 207 ms; n = 5; P < 0.05; Wilcoxon T test). This enhancement was dependent upon NMDA receptor activation since AP5 (50 µM) completely blocked the plateau potential, even in the presence of BayK 8644 (n = 5; not shown). Next, cortically evoked membrane potential oscillations were examined. Figure 8A shows cortically evoked membrane potential oscillations in a medium spiny neuron in the presence of NMDA. Bath application of BayK 8644 increased the duration of the up-states from 0.9 ± 0.08 s in the control (with NMDA) to 2.1 ± 0.2 s in BayK 8644 (Fig. 8B, n = 6, P < 0.03; Wilcoxon T test). BayK 8644 also significantly depolarized the modal up-state potential without affecting the down-state potential (Fig. 8C, n = 6, P < 0.05). Taken together, these data provide compelling evidence that, under certain conditions, L-type Ca²⁺ channels may work in concert with NMDA receptors to create a condition permissive for the expression of bistability in medium spiny neurons.

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Figure 8. L-type Ca²⁺ channel agonist, BayK 8644, increased the duration of membrane potential oscillations
A, membrane potential oscillations were evoked by cortical stimulation plus NMDA (20 µM; control). Addition of BayK 8644 (5 µM) increased the duration of up-state events (+BayK 8644 and B). C, the amplitude of these events was also increased after BayK 8644 (C).

Blockade of GABA_A receptors enhanced the duration of the up-states

What controls the duration of the up-state? Active inhibitory processes mediated by GABA_A receptors are one possibility. In agreement with this hypothesis, the local application of the GABA_A receptor antagonist picrotoxin increased the duration of up-states (Fig. 9A and B). The up-state duration in a sample of control neurons was 0.9 ± 0.1 s, while it was 2.9 ± 0.7 s in the presence of either picrotoxin (10 µM) or bicuculline (2 µM) (P < 0.03, n = 6, Wilcoxon T test) (Fig. 9, right). This result suggests that fast GABAergic transmission controls the duration of the up-states (Klausberger et al. 2003)

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Figure 9. GABA_A receptor antagonists enhance up-state duration
A, membrane potential oscillations were induced by repetitive cortical stimulation plus NMDA (10 µM). B, the duration of up-states was enhanced by the addition of GABA_A receptor antagonists to the bath saline (+picrotoxin, 5 µM). C, box plots illustrate distributions of up-state duration before and during the GABA_A receptor antagonists picrotoxin and bicuculline (5 µM) in a sample of neurons (n = 6).

DISCUSSION

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Abstract
Introduction
Methods
Results
Discussion
References

The principal finding of this study was that, in the slice, cortical stimulation is capable of evoking membrane potential oscillations in striatal medium spiny neurons. Once initiated, these oscillations continued without overt cortical stimulation resembling up- and down-voltage transitions seen in vivo and in organotypic cultures (Wilson, 1993; Wilson & Kawaguchi, 1996; Stern et al. 1997; Plenz & Kitai, 1998; Wang & O'Donnell, 2001). Interestingly, similar stimuli also evoke voltage transitions in cortical slice preparations (Shu et al. 2003). Although previous studies have shown that cortical or white matter stimulation is capable of evoking plateau potentials in medium spiny neurons (Wilson et al. 1983; Bargas et al. 1991; Galarraga et al. 1997; Schlosser et al. 1999), the relation of these plateau potentials with subsequent voltage oscillations had not been described. It is shown that oscillations can be controlled by both intrinsic and circuit-based factors. Transitions to the up-state were promoted by augmentation of inward currents carried by NMDA receptors and L-type Ca²⁺ channels and suppressed by currents carried by GABA_A receptors and TEA-sensitive K⁺ channels.

Several physiological oscillatory phenomena have been described during brain activity. Their generating mechanisms may vary and, moreover, distinct kinds of oscillations may coalesce (e.g. Szabadics et al. 2001; Bevan et al. 2002; Steriade & Timofeev, 2003). Studies in the slice preparation are just beginning to classify and study these phenomena. Thus, some studies stress the predominance of synaptic and network variables (e.g. Szabadics et al. 2001; Shu et al. 2003), others underscore the importance of intrinsic neuronal properties (Hsiao et al. 1998; Traub et al. 2003), and still others report a mixed participation of intrinsic and synaptic factors (Guertin & Hounsgaard, 1998; Bevan et al. 2002). Although much remains to be done, the oscillations described here can be listed in the last group. We have identified ionic conductances that appear to facilitate the generation of oscillations. However, the activation of voltage-dependent conductances ultimately depends on network synaptic activity most probably originating on the synaptic membrane at the dendrites. It was shown that NMDA receptors play a key role to interlock synaptic and intrinsic components. L-type Ca²⁺ channels are present and functional at subthreshold voltages in medium spiny neostriatal neurons (Perez-Garci et al. 2003) and are able to induce plateau potentials, bistability and voltage fluctuations between two membrane potentials. They can be activated by synaptic inputs if their temporal profile is appropriate (Galarraga et al. 1997). Therefore, it is a matter of future research to determine when and how these ion channel machinery plays a physiological role.

Certain conditions may be necessary to observe these phenomena in vitro. First, by tracking corticostriatal afferent fibres in parasagittal slices with anterograde biocytin transport, the most probable connected regions of the cortex and striatum were identified in these slices and targeted for stimulation and recording. Next, bathing solutions with K⁺ and Ca²⁺ concentrations that more closely resemble those thought to exist in vivo (Sanchez-Vives & McCormick, 2000) were used. In these conditions, stimulation of cortical afferent fibres was capable of evoking plateau potentials and up- and down-type of voltage oscillations in a subset of medium spiny neurons.

The oscillations seen in the slice have both similarities and differences with those seen in vivo. There are a number of similarities: up-states depended upon excitatory synaptic input (cf. Wilson, 1993; Stern et al. 1997). Neither plateau potentials nor oscillations could be evoked with somatic current injections - in contrast to the case of motoneurons (Perrier & Hounsgaard, 2000). As in vivo, the up-state seen in the slice had a preferred membrane potential range near -50 mV, just below spike threshold. The down-state potentials during cortically induced oscillations in the slice, were unimodally distributed (Wilson, 1993; Stern et al. 1997). Up-state durations in vitro, during nominally autonomous oscillations, were also similar to those reported in anaesthetized animals, ranging from a few hundred milliseconds to seconds. Furthermore, both in vivo and in vitro up-states are aperiodic and triggered irregular spiking. These similarities argue that at the very least, there are some common mechanisms governing membrane potential oscillations in the slice preparation and in vivo. Nevertheless, differences were also observed: in vivo, inward current antagonists administered through the recording sharp electrode did not affect the voltage oscillations (Wilson, 1993; Wilson & Kawaguchi, 1996; Stern et al. 1997). The range of membrane potentials during the down-state is larger in vitro than in vivo, with a tendency towards more depolarized potentials. Noticeably, the facilitatory actions of NMDA, when tested in vivo, had a depolarizing effect on the membrane potential (Herrling et al. 1983). This was also true for trains of repetitive stimuli in other systems (Steriade & Timoofev, 2003). Most importantly, although the addition of exogenous NMDA may partially activate synaptic receptors normally activated by cortical inputs, it does not substitute for bi-dimensional spatial activation of impaired contacts (Kilb & Luhmann, 2003) or for contacts coming from important afferents such as the thalamus and the subthalamic-pallidal network (Bevan et al. 2002).

Another reason for the differences found with in vivo oscillatory activity might be the anaesthetics used. Anaesthetics are known to potentiate GABAergic signalling and impair NMDA or AMPA signalling in different degrees (Richards, 2002). NMDA and GABAergic synaptic mechanisms were shown here to be critical for the emergence of bistability in the slice preparation. It is not difficult to see how changes in these synaptic actions might tend to suppress intrinsic mechanisms and shift the neurons towards a more extrinsically dependent activity. In other neurons, the intrinsic mechanisms supporting bistability are weakened by an enhancement of dendritic GABAergic inputs (e.g. Miura et al. 1997).

Finally, it was hard to find synchronicity with surrounding neurons (J. Bargas, unpublished observations). This again is explained by a reduced number of synaptic contacts by Cossart et al. (2003) who show that, in the slice, only a few neurons out of hundreds are firing synchronously. Partial confirmatory experiments of this hypothesis have recently been published (Kilb & Luhmannn, 2003): up-state frequency decays when recordings are performed in the slice, instead of 'intact cerebral cortex' preparations.

Nonetheless, both previous studies and the present work agree in that medium spiny neurons lack somatic bistability as a determinant of plateau potentials or voltage oscillations. The present work shows evidence that medium spiny neurons most probably turn bistable due to dendritically located conductances. An NMDA-mediated synaptic mechanism appears to trigger an intrinsic mechanism mediated by L-type Ca²⁺ channels (Schiller & Schiller, 2001). Synaptic integration includes the generation of plateau potentials and membrane potential oscillations. These observations allow the cautious conclusion that oscillatory phenomena observed under the present conditions may represent a subset of a larger spectrum of oscillatory activities (Bevan et al. 2002; Steriade & Timoofev, 2003). This intrinsic mechanism could have profound implications for striatal integration by dissociating the duration of cortical input from the duration of striatal output under certain circumstances.

Plateau potentials and up-states in the slice are dependent upon NMDA receptors

Our results show that synaptic input may trigger prolonged depolarizing events. Plateau potentials in the slice were eliminated by blockade of either AMPA/KA receptors with CNQX or NMDA receptors with AP5. Furthermore, short trains of cortical synaptic inputs similar to those seen with temporally convergent inputs in vivo were effective triggers of plateau potentials and subsequent voltage oscillations. The linkage between synaptic activation and plateau potentials was strengthened by the ability of exogenous NMDA to enhance the generation of plateau potentials from near threshold EPSPs. Repetitive cortical stimulation in the presence of micromolar concentrations of NMDA in the bath was the most effective protocol to trigger membrane potential transitions. This concentration of NMDA was sufficient to create a region of negative slope conductance and a second positive slope crossing the I-V relationship of medium spiny neurons. These phenomena are the landmark of membrane potential bistability (Booth et al. 1997; Kiehn & Eken, 1998; Hsiao et al. 1998; Lee & Heckman, 1998b; Carlin et al. 2000; Schiller & Schiller, 2001; Svirskis et al. 2001). In fact exogenous NMDA in conjunction with synaptic input is a potent inducer of membrane potential bistability and voltage oscillations in other preparations (Guertin & Hounsgaard, 1998; review in Schiller & Schiller, 2001). The conjunction of NMDA and synaptic input presumably serves to selectively enhance the slower NMDA component of the naturally occurring synaptic potential profile, leading to the activation of intrinsic voltage-dependent conductances (Larkum et al. 2001; Schiller & Schiller, 2001). In medium spiny neurons, this interaction is likely to be occurring in the dendrites, where the vast majority of excitatory inputs are located (Wilson, 1993). This inference is consistent with the ability of Kir₂ channel blockade with Ba²⁺ to substantially shift the negative slope region toward more negative membrane potentials.

L-type Ca²⁺ channels contribute to synaptically driven plateau potentials and membrane potential oscillations

Which dendritic conductances are engaged by synaptic input in medium spiny neurons? Because the voltage range in which Mg²⁺ block is relieved overlaps with the activation range for a number of inward conductances, NMDA currents could interact with several channel types. One of these is the L-type Ca²⁺ channel. L-type Ca²⁺ channels are essential to fix the tonic firing pattern, the input-frequency relationship (dynamic range) and the firing threshold of medium spiny neurons (Perez-Garci et al. 2003). In a number of neurons, plateau potentials and voltage oscillations triggered by NMDA receptor activation are dependent upon L-type Ca²⁺ channels (Seamans et al. 1997; Schwindt & Crill, 1997; Guertin & Hounsgaard, 1998; Russo & Hounsgaard, 1999; Schiller & Schiller, 2001). The situation appears to be similar in medium spiny neurons (Galarraga et al. 1997; Cepeda et al. 1998; Akopian & Walsh, 2002) in which dopamine modulation greatly resides in their Ca²⁺-channels (Hernández-Lopez et al. 1997, 2000). This work shows that plateau potentials and subsequent voltage oscillations are dependent upon L-type Ca²⁺ channels, as their blockade abolished both phenomena. Conversely, facilitation of L-type currents with BayK 8644 enhanced the duration and frequency of up-states evoked by cortical stimulation.

Low threshold L-type channels in proximity to NMDA receptors seem particularly important in the generation of plateau potentials (Seamans et al. 1997; Schwindt & Crill, 1997, 1998; Guertin & Hounsgaard, 1998; Carlin et al. 2000; Schiller & Schiller, 2001). These L-type Ca²⁺ channels need to be present at only a few dendritic branches for bistability to emerge (Svirskis et al. 2001). The dependence of the NMDA-induced negative slope conductance region on L-type channels is consistent with the proposition that these channel types are co-localized in dendritic regions and critical to the up-state. Medium spiny neurons co-express Cav1.2 and Cav1.3 channels and have a prominent low threshold L-type current (Bargas et al. 1994; Olson et al. 2001; Perez-Garci et al. 2003), but further study will be required to determine which of these channel types is critical to this interaction with NMDA receptors. Nevertheless, it is clear that dendritic L-type Ca²⁺ channels are capable of shaping the responses to excitatory synaptic input in medium spiny neurons.

What is more perplexing is the ability of brief repetitive cortical stimulation to induce lasting oscillations in the membrane potential of medium spiny neurons. These oscillations continue without overt extrinsic cortical stimulation for up to 1 h or more in some cases. Oscillations were not obviously periodic in most neurons. One hypothesis is that the inducing stimulation set up cortical oscillations that continued to drive striatal state transitions (Kilb & Luhmann, 2003). Another possibility is that the oscillations, although triggered by cortical stimulus, depend upon striatal mechanisms for their maintenance. What these mechanisms might be are unclear at these moment.

Conclusions

Cortical stimulation of striatal medium spiny neurons in tissue slices is capable of evoking plateau potentials and sustained oscillatory activity bearing a strong resemblance to state transitions seen in vivo. The plateau potentials and up-state transitions were dependent upon NMDA receptors and L-type Ca²⁺ channels. The data presented clearly implicate intrinsic mechanisms in the up-state transitions and argue that dendritic regions of medium spiny neurons exhibit conditional bistability.

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Acknowledgements

We are grateful to C. Vilchis and D. Tapia for technical help. This work was supported by CONACyT (Mexico) and Millenium Research Initiative grants: 31839-N and W-8072 (35806-N) to J.B. and E.G., DGAPA-UNAM grants IN 202100 to E.G. and IN 202300 to J.B., NIH grants NS34696 and DA12958 to D.J.S. and FIRCA-NIH grant TWO1214 to D.J.S., J.B. and E.G.

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Spontaneous voltage oscillations in striatal projection neurons in a rat corticostriatal slice

R. Vergara, C. Rick*, S. Hernández-López*, J. A. Laville, J. N. Guzman, E. Galarraga, D. J. Surmeier* and J. Bargas

R. Vergara, C. Rick, S. Hernández-López, J. A. Laville, J. N. Guzman, E. Galarraga, D. J. Surmeier* and J. Bargas