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Department of Pharmacology, University of Connecticut Health Center, Farmington, CT 06030, USA
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Abstract |
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(Received 8 December 2003;
accepted after revision 21 January 2004;
first published online 23 January 2004)
Corresponding author E. S. Levine: Department of Pharmacology, MC-6125, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, USA. Email: eslevine{at}neuron.uchc.edu
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Introduction |
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The cortical endocannabinoid system is well-suited to regulate specific inhibitory domains because CB1R expression is mostly restricted to the subset of GABAergic interneurones that coexpress cholecystokinin (CCK; Marsicano & Lutz, 1999). Interneurones that express CCK target the perisomatic membrane of PNs (Kubota & Kawaguchi, 1997; Kawaguchi & Kubota, 1998). In the hippocampus, CB1R is also expressed in CCK-positive basket cells (Katona et al. 1999; Tsou et al. 1999) and DSI-sensitive currents tend to be large-amplitude events with fast rise times, consistent with somatic localization (Martin et al. 2001; Wilson et al. 2001). Interestingly, cholinergic receptor activation selectively enhances hippocampal DSI partly by increasing the discharge of CCK-expressing interneurones (Martin & Alger, 1999). In the cortex, CCK-expressing interneurones are also depolarized by cholinergic agonists (Kawaguchi, 1997). Cortical endocannabinoids may preferentially modulate GABA release from the subset of CCK-expressing interneurones, thereby selectively suppressing perisomatic inhibition.
Although the cannabinoid system in the neocortex mediates many of the cognitive and behavioural effects of marijuana, there has been little study of the cortical endocannabinoid system. We have recently shown that CB1R activation suppresses GABA release from cortical interneurones (Trettel & Levine, 2002), consistent with the effects of exogenous cannabinoids on GABA release in frontal cortex in vivo (Ferraro et al. 2001). We have also shown that endocannabinoids mediate a DSI-like phenomenon of evoked inhibitory currents in neocortex (Trettel & Levine, 2003). Evoked currents, however, represent the synchronous activation of a heterogeneous population of synapses arising from diverse cell types, and the change in amplitude provides little information regarding the inputs that are suppressed. In order to understand the physiological significance of this retrograde synaptic signalling, an important first step is to identify the specific inhibitory inputs that are modulated by endocannabinoid-mediated DSI. In the present studies we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) and postsynaptic potentials (sIPSPs) to characterize DSI-susceptible afferents and to determine the spatial distribution of their synaptic contacts on the postsynaptic PN membrane.
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Methods |
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Swiss CD-1 mice (P12-20; Charles River) were killed by exposure to a rising concentration of CO2 followed by rapid decapitation according to procedures approved by University of Connecticut Health Center Animal Care Committee. Brains were rapidly dissected into ice-cold cutting saline that was composed of (mM): 125.0 NaCl, 2.5 KCl, 1.25 NaH2PO4, 25.0 NaHCO3, 0.5 CaCl2, 4.0MgCl2, 17.5 glucose and gassed with 95% O2–5% CO2 (pH 7.3, 315 ± 3mmol kg–1 osmolality). The tissue was then sectioned at 300µm (DTK-1000, Dosaka) in the anatomically transverse plane. Cortical slices containing auditory and visual fields (Frisina & Walton, 2001; Paxinos & Franklin, 2001) were incubated for 30–45 min in a custom submersion-type recovery chamber that was filled with normal saline at 35°C. These granular, sensory regions were easily demarcated from surrounding cortical fields by the relative packing density of neurones and the robustness of layer 4. The normal saline, or artificial cerebrospinal fluid (ACSF), was composed of (mM): 125.0 NaCl, 2.5 KCl, 1.25 NaH2PO4, 25.0 NaHCO3, 2.0 CaCl2, 2.0MgCl2, 17.5 glucose and gassed with 95% O2–5% CO2 (pH 7.3, 315 ± 3mmol kg–1). After recovery, the slices were subsequently transferred to a recording chamber fixed to the stage of an upright microscope that was perfused with fresh oxygenated saline (32 ± 0.5°C) and allowed to acclimate for 5–10 min prior to recording.
Electrophysiology
Whole-cell recordings of sIPSCs and sIPSPs were made from layer 2/3 PNs. Ionotropic glutamate receptors were blocked with bath perfusion of 6,7-dinitroquinoxaline-2,3-dione (DNQX, 10µM, Tocris, Bristol, UK) and 3-((R)-2 - carboxypiperazin - 4-yl)-propyl-1-phosphonic acid (CPP, 2µM, Tocris). Individual neurones were visualized using an Olympus BX51W microscope equipped with infrared differential interference contrast optics. All neurones in our sample had the characteristic pyramidal-shaped soma with a single apical dendrite; PNs responded to depolarizing current injection with regular, frequency-adapting spikes that are typical of these neurones (e.g. McCormick et al. 1985; Connors & Gutnick, 1990).
Voltage clamp recordings were made with borosilicate glass micropipettes (pipette resistance (Rp) = 3–5M
) filled with (mM): 120.0 CsCl, 10.0 Hepes, 1.0 EGTA, 0.1 CaCl2, 1.5MgCl2, 4.0 Na2-ATP, 0.3 Na-GTP and 5.0 QX-314 (pH 7.3, 293±2mmol kg–1). Prior to use the glass pipettes were lightly heat polished. Synaptic currents were filtered at 2.9kHz and digitized at 
6kHz using a HEKA EPC9/2 amplifier and a PCI-16 interface board (Heka Elektronic, Darmstadt, Germany). Neurones were voltage clamped at –70mV. Upon breaking into whole-cell configuration, a brief series of voltage ramps (50ms, 2mVms–1) were applied to promote the activity-dependent block of Na+ conductances by QX-314 (Sigma, Missouri, USA). Series resistance (Rs) was then compensated to 60% or greater at 10–100µs lag. During the course of the experiments, leak currents were subtracted online (P/4) and the input resistance (Ri) was monitored continuously with 5mV hyperpolarizing voltage steps (50ms). Neurones were rejected from analyses if: (1) Rs was >25M at the time of break-in or >10.5M after compensation, (2) Ri changed by >15% during the course of an experiment, or (3) Ri fell below 100M. For current clamp recordings, the internal pipette solution contained (mM): 130 KCl, 0.10 CaCl2, 10 Hepes, 1 EGTA, 4 Na2-ATP, 0.3 Na-GTP and 10 phosphocreatine (pH 7.3, 285±2mmol kg–1). Brief trains of action potentials (20 Hz) were induced by injecting square-wave current pulses (pulse duration = 5ms; amplitude = 1 nA). Cells were rejected from the analysis if: (1) Vm was below –60mV, (2) Ri changed by >15% during the course of an experiment, or (3) Ri fell below 100M.
GABA and bicuculline (BIC) were focally applied to PN membranes with unpolished glass recording pipettes. GABA (100µM, pH 3.2) was iontophoretically applied (25–50 nA ejection, –15 nA retention; ION-100, Dagan) and BIC (150µM) was pressure applied at 5–30 kPa (Picospritzer II, Parker Hannifin). The pipette tips were placed 
15µm from the membrane surface during iontophoresis and 25µm from the membrane surface during pressure ejection. Duration of drug application was 10–50ms. All other drugs were delivered through the bath perfusion system at 2–3 ml min–1. WIN55,212-2 (Sigma), AM251 (gift from Dr A. Makriyannis, University of Connecticut) and DNQX were stored in 10 mM aliquots in DMSO at –20°C. Final DMSO concentration did not exceed 0.03%.
Data analysis
Off-line analysis was carried out using PulseFit (Heka Elektronic), MiniAnalysis (Synaptosoft, Georgia, USA), and Origin (Origin Laboratories, Northampton, MA, USA) software. MiniAnalysis was used to detect spontaneous synaptic events and generated most of the parameters that were used in the analyses. To quantify IPSCs, we integrated the area of individual IPSCs within specified bins to determine the total synaptic charge (Q; pAms). This measure captures changes in both the frequency and the amplitude of synaptic events. For voltage clamp recordings, DSI was analysed by comparing the Q of all events in a 10 s bin before depolarization with the Q during a 10 s bin after depolarization. The first 2 s following the voltage step were disregarded to allow maximal DSI to develop. The percentage charge suppression (i.e. DSI) was calculated as: DSI =[1 – (Qpost/Qpre)]x 100. Therefore, a value of 78 indicates a 78% decrease in Q following the depolarizing voltage step. For current clamp recordings, baseline sIPSP activity was calculated by averaging the total area in a 10 s bin prior to delivery of the action potential train. Each 5 s bin immediately following the train was then compared to baseline using the above equation (substituting area for charge). Amplitude distributions for sIPSCs were tested for significance using Kolmogorov-Smirnov statistics (K-S). All other data were compared using repeated measures ANOVAs or Student's paired t tests and presented as mean ±S.E.M.
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Results |
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Recently we have shown that DSI of evoked IPSCs in the neocortex is mediated by activation of presynaptic CB1Rs on GABAergic interneurones (Trettel & Levine, 2003), similar to the hippocampus and the cerebellum (Kreitzer & Regehr, 2001; Wilson & Nicoll, 2001; Diana et al. 2002; Yoshida et al. 2002). Moreover, CB1R mRNA expression in the neocortex is mostly restricted to a specific class of interneurones that synthesize CCK (Marsicano & Lutz, 1999). Because muscarinic receptor activation has been shown to directly depolarize CCK-expressing interneurones in the neocortex (Kawaguchi, 1997), we used the cholinergic agonist carbamylcholine chloride (CCh) to elevate the spontaneous activity of these cells. As shown in the example in Fig. 1A, bath application of CCh (5µM) produced a 4-fold increase in sIPSC charge (Fig. 1B; P<0.05; n= 6). The effect of CCh was blocked by atropine (2µM; data not shown), indicating that muscarinic receptor activation was responsible. To verify that CCh increased the activity of CB1R-containing cells, we bath-applied an exogenous cannabinoid during CCh exposure. In the presence of WIN55,212-2 (5µM), sIPSC charge dropped to 43 ± 5.5% of the CCh baseline (Fig. 1A and B; P < 0.05; n= 6), which was not significantly different from the mean charge prior to the addition of CCh. These data indicate that a majority of CCh-sensitive interneurones express CB1R.
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Depolarization-induced suppression of sIPSCs
In the presence of CCh, PN depolarization (–70 to 0mV; 1s) caused a dramatic and transient suppression of sIPSCs (i.e. DSI; Fig. 2A and D). The distribution of sIPSC amplitudes in the presence of CCh revealed the presence of a newly recruited population of inputs that had large amplitudes and were selectively eliminated after the postsynaptic voltage step (Fig. 2B, compare baseline and post DSI distributions). In a group of eight cells, the mean value of DSI was 71.6 ± 3.4% (Fig. 2E, P < 0.05). We next examined whether endocannabinoids mediated the suppression of CCh-stimulated sIPSCs. The effect of the PN voltage step on synaptic currents was blocked when the CB1R antagonist AM251 (5µM) was present (Fig. 2C, D and E; n= 5). As illustrated in Fig. 2D, no significant change in sIPSC charge occurred following the voltage step in the presence of AM251, whereas significant suppression in control cells lasted for 18 s. AM251 alone had no effect on sIPSC charge (data not shown). Similarly, if the suppression of sIPSCs required CB1R signalling then activation of CB1R with an exogenous agonist should occlude the effects of depolarization. As shown in Fig. 2E, preincubation of the brain slices in ACSF containing the cannabinoid receptor agonist WIN55,212-2 (5µM) blocked DSI (n= 9).
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Because other metabotropic signalling systems have also been implicated in DSI, we explored the involvement of mGluR and GABAB receptor activation in the endocannabinoid-mediated suppression of sIPSCs. Blocking group I and II mGluRs with a cocktail of the group II antagonist LY341495 (75µM) and the mixed group I/II antagonist MCPG (1 mM) resulted in DSI that was not significantly different from DSI in the presence of CCh (Fig. 2E and 60.2 ± 4.8%; n= 7). Similarly, blocking GABAB receptors with the high affinity antagonist CGP35348(65µM) also did not change the magnitude of DSI compared to CCh alone (Fig. 2E and 65.3 ± 7%, n= 5). These data confirm that CB1R activation is required for sIPSC suppression and neither mGluR nor GABAB receptor activation contribute to the induction or expression of endocannabinoid-mediated DSI in the neocortex under these conditions.
Induction of DSI by action potentials
We next asked whether a train of APs, rather than sustained membrane depolarization, could lead to a suppression of inhibition. For these experiments, APs were evoked at 20 Hz, a frequency that is similar to the PN firing rates observed in vivo (Steriade, 2000). Under current clamp conditions, adding CCh to the bath sharply increased the frequency of GABAA-mediated spontaneous inhibitory postsynaptic potentials (sIPSPs) from 1.77 ± 0.3 to 4.85 ± 0.5 Hz (data not shown; P < 0.05; n= 7). Following a single 20 Hz AP train (train duration = 1 s), sIPSP area was suppressed by 89 ± 2.3% during the 5 s period following the AP train and returned to baseline levels within 15–20 s (Fig. 3A and D; P < 0.05; n= 6). Similar to the results obtained in voltage clamp, the AP train induced a marked suppression of large amplitude sIPSPs (Fig. 3C). To determine if the suppression of sIPSPs was mediated by the release of endocannabinoids, we bath-applied a CB1R antagonist. In the presence of AM251 (5µM), the AP train failed to induce significant sIPSP suppression (Fig. 3B and D and 8.0 ± 9.8%; n= 6).
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The spatial location of an inhibitory synapse on a target neurone will partly determine the roles that that synapse, and hence that presynaptic neurone, will play in influencing the activity and synaptic integration properties of the postsynaptic cell. In order to resolve the approximate location of DSI-susceptible synapses, we used focal application of the GABAA antagonist BIC to isolate distinct domains of the PN membrane. Neurones used for these experiments were located deep in layer 3 and had clearly visible apical dendrites extending into layer 1. To validate this experimental approach, GABA was iontophoretically applied at the perisomatic and distal apical dendritic regions, while BIC was applied close to the soma (Fig. 4A). Consistent with electrotonic decay, the slope and amplitude of the GABA current (IGABA) progressively decreased as the iontophoretic electrode was moved from the soma towards the distal apical dendrite (see example in Fig. 4B). However, the contribution of site-dependent heterogeneity in GABAA receptor subunit expression to the difference in slope and amplitude of IGABA cannot be ruled out. On average, the amplitude of the somatic IGABA was 2.63 ± 1.11 nA (n= 4) compared to 0.45 ± 0.17 nA (n= 4) for the dendritic IGABA elicited >80µm distal from the soma. After obtaining stable IGABA at both locations, BIC was ejected onto the soma. As shown in Fig. 4C, BIC application abolished the perisomatic IGABA(4.2 ± 2.1% of baseline; n= 4) but had no effect on dendritic IGABA (96.2 ± 3% of baseline; n= 4). These results demonstrate that GABAA receptors and presumably GABAergic inputs on the apical dendrite can be isolated from those on and near the soma by focally applying BIC.
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The kinetics of sIPSCs will change systematically as a function of distance from the recording pipette due to the electronic properties of the neural membrane (Segev & London, 1999). Therefore, we also analysed sIPSC rise times (10–90%) in the same set of cells presented in Fig. 5. The somatic voltage step (DSI) shifted the rise time distribution towards slower sIPSCs (Fig. 6A), producing a significant increase in the mean rise time (Fig. 6D and 119.4 ± 6.6% of baseline; P < 0.05, n= 8). Somatic BIC produced a similar change in sIPSC rise times, increasing the mean value to 136.4 ± 7.4% of baseline (Fig. 6B and D; P < 0.05, n= 8). In contrast, apical BIC selectively blocked sIPSCs with slow rise times, significantly reducing the mean to 88.4 ± 3.2% of baseline (Fig. 6C and D; P < 0.05; n= 8). The preservation of sIPSCs with fast rise times (typically less than 2ms) indicates that dendritic BIC selectively blocked inputs to the apical dendrites. Taken together, these data suggest that DSI preferentially suppressed synapses that target the perisomatic membrane of PNs.
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Discussion |
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Our first goal was to establish whether a specific subclass of inhibitory afferents to layer 2/3 PNs are susceptible to DSI. Pyramidal neurones are innervated by several distinct types of interneurones that form synapses on segregated domains of the target PN. Under baseline conditions, significant suppression of inhibition was observed, but only a fraction of the spontaneous synaptic currents appeared to be affected. Since muscarinic receptor activation has been shown to selectively depolarize CCK-expressing (and presumably CB1R-expressing) interneurones (Kawaguchi, 1997), we bath-applied CCh in order to increase the firing rate of these interneurones. Similar to results obtained in the hippocampus (e.g. Martin et al. 2001) and frontal cortex (Kondo & Kawaguchi, 2001), carbachol greatly increased sIPSC activity in sensory neocortex. In particular, CCh increased AP-dependent activity in a subpopulation of afferents that generated large amplitude synaptic currents with rapid rise times. Furthermore, the inputs recruited by CCh were particularly susceptible to DSI – these currents were almost completely inhibited in response to postsynaptic depolarization. This effect was mediated by release of an endocannabinoid because it was blocked by a CB1R antagonist and occluded by a CB1R agonist. Moreover, DSI was unaffected by antagonists to metabotropic glutamate and GABA receptors. It is also important to note that muscarinic receptor activation, besides increasing interneurone firing, may enhance endocannabinoid production (Kim et al. 2002), and this may play a role in the enhanced DSI seen in the presence of CCh.
As most studies of DSI have used prolonged depolarization to induce suppression, the physiological relevance of this phenomenon is unclear. In the hippocampus, there have been conflicting reports regarding the ability of AP trains to induce DSI (Pitler & Alger, 1992; Ohno-Shosaku et al. 2001; Hampson et al. 2003). We therefore asked whether APs were sufficient to elicit DSI in the neocortex. We found that cortical DSI was reliably induced with a 20 Hz train of action potentials. This AP-triggered DSI was blocked by a CB1R antagonist, indicating that it was mediated by the release of an endocannabinoid. These results suggest that physiologically relevant levels of action potential firing alone are capable of inducing endocannabinoid-mediated DSI in the neocortex. The magnitude and duration of DSI caused by a 1 s train of APs at 20 Hz was similar to that seen using a 1 s depolarization to 0mV. Thus, it may be possible to use more physiological induction parameters to address questions about the functional role of DSI in synaptic transmission. Further studies are needed to determine the minimal, or threshold level of activity required to induce endocannabinoid release in the cortex, as well as to address potential differences between cortical and hippocampal DSI with regard to AP induction.
We next investigated the spatial distribution of DSI-susceptible synaptic inputs to layer 2/3 PNs. Anatomical studies have shown that expression of CB1R in the neocortex, as well as in the hippocampus, is mostly limited to GABAergic interneurones that express CCK (Marsicano & Lutz, 1999; Egertova & Elphick, 2000). CCK-positive GABAergic interneurones are basket cells, typically forming synapses on the soma and proximal dendrites of PN targets. In the present studies, we found that the synaptic currents suppressed by depolarization had faster rise times and larger amplitudes than the currents that were not suppressed, suggesting a perisomatic localization. These results are similar to those obtained in the hippocampus (Martin et al. 2001; Wilson et al. 2001).
We also directly examined the spatial distribution of these afferents using local application of the GABAA antagonist BIC. By applying BIC focally at either the soma or apical dendrites, we were able to clearly separate inhibitory somatic events from inhibitory dendritic events. When applied at the pyramidal cell soma, BIC preferentially suppressed large, fast IPSCs, similar to the effects of depolarization. Conversely, application of the antagonist in the apical dendrites of PNs suppressed small, slow currents, similar to the sIPSCs that were generally unaffected during DSI. Thus, both somatic and dendritic BIC were effective in blocking distinct populations of inhibitory inputs, but only somatic BIC mimicked the effects of DSI. Taken together, these studies provide evidence that depolarization-induced cannabinoid release selectively suppresses GABA release from perisomatic inhibitory afferents. These cells most likely constitute a class of CCK/CB1R-expressing basket cells.
What are the functional implications of selectively suppressing perisomatic inhibition? Inhibitory synapses on different domains of PNs in both cortex and hippocampus modulate distinct aspects of activity (Soltesz et al. 1995; Miles et al. 1996; Somogyi et al. 1998; Larkum et al. 1999; Williams & Stuart, 2003). Synapses on or near the axon hillock can directly modulate action potential generation by providing a high conductance current shunt near the site of summation. Other inhibitory inputs that target distal dendrites can influence neuronal responsiveness to excitatory inputs by modulating the local membrane potential and altering the passive membrane properties by dynamically changing the local membrane conductance. Inhibitory somatic inputs, on the other hand, provide potent and tonic inhibition that can regulate action potential timing by effectively blocking the spread of depolarization towards the hillock. Somatic inhibition could also regulate the back-propagation of action potentials into the dendritic arbor; back-propagation in PNs is critical for synaptic integration and plasticity as well as burst mode firing (Larkum et al. 1999). Therefore, a function of endocannabinoid-mediated DSI in the neocortex may be to alter the integrative properties of PNs by selectively and potently removing one form of somatic inhibition.
Modulation of CCK release may also mediate some of the physiological effects of cannabinoids. The CB1R-expressing interneurones presumably use CCK as a cotransmitter, and potassium-evoked CCK release in the hippocampus is inhibited by CB1R activation (Beinfeld & Connolly, 2001). There is also evidence that the release of CCK and GABA can be differentially regulated in presynaptic terminals (reviewed in Ghijsen et al. 2001), thus it could be important to compare the effects of CB1R activation on the release of each transmitter under various physiological conditions. Little is known about the cellular effects of activating the CCK-B receptor in neurones, but CCK may decrease postsynaptic firing by stimulating A-type potassium channels (Burdakov & Ashcroft, 2002). CCK and cannabinoids appear to have contrasting roles in several brain functions, including spatial memory (Jentsch et al. 1997; Sebret et al. 1999; Beinfeld & Connolly, 2001), supporting the idea that some of the effects of cannabinoids may result from decreased CCK release.
Because retrograde endocannabinoid signalling appears to regulate a specific class of inhibitory inputs, it may be interesting to examine whether other classes of inputs to pyramidal cells can also be modulated by retrograde signalling. It has been shown, for example, that dendritic glutamate release suppresses the activity of fast spiking interneurones in the neocortex (Zilberter, 2000). These fast spiking cells preferentially target the dendritic membrane of PNs (Kawaguchi & Kubota, 1996) and are thought to play a role in synaptic integration (Somogyi et al. 1998). Thus, different patterns of PN firing may release retrograde signals from either the soma or dendrites, thereby shifting the focus of inhibition from one cellular compartment to another.
Overall, the present results indicate that cortical PNs release endocannabinoids in response to depolarizing stimuli, including short trains of action potentials. Endocannabinoids act in a retrograde manner to suppress GABA release from presynaptic terminals, specifically targeting perisomatic afferents that presumably arise from CCK-expressing interneurones. The selective suppression of these inputs by endocannabinoids would likely have important functional consequences for PN processing and therefore, the output of the neocortex.
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