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¹ Division of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA

Because the hyperpolarization-activated cation-selective current I_h makes important contributions to neural excitability, we examined its long-term regulation by vitronectin, an extracellular matrix component commonly elevated at injury sites and detected immunochemically in activated microglia. Focusing on mouse hippocampal pyramidal neurones in organotypic slice cultures established at postnatal day 0 or 1 and examined after 3–4 days in vitro, we observed differences in the amplitude and activation rate of I_h between neurones in naive and vitronectin-exposed slices (10 µg ml^–1 added to serum-free medium), and between neurones in slices derived from wild-type and vitronectin-deficient mice. The potassium inward rectifier I_K(ir), activated at similar voltages to I_h, was not affected by vitronectin. In CA1, differences in I_h amplitude primarily reflected changes in maximum conductance (G_max): a 23.3% increase to 3.18 ± 0.64 nS from 2.58 ± 0.96 nS (P < 0.05) in vitronectin-exposed neurones, and a 17.9% decrease to 2.24 ± 0.26 nS from 2.73 ± 0.64 nS (P < 0.05) in neurones from vitronectin-deficient slices. The voltage of one-half maximum activation (V) was not significantly affected by vitronectin exposure (–78.1 ± 2.3 mV versus –80.0 ± 4.9 mV in naive neurones; P > 0.05) or vitronectin deficiency (–83.8 ± 3.1 mV versus –82.0 ± 2.9 mV in wild-type neurones; P > 0.05). In CA3 neurones, changes in I_h reflected differences in both G_max and V: in vitronectin-exposed neurones there was a 35.4% increase in G_max to 1.30 ± 0.49 nS from 0.96 ± 0.26 nS (P < 0.01), and a +3.0 mV shift in V to –89.8 mV from –92.8 mV (P < 0.05). The time course of I_h activation could be fitted by the sum of two exponential functions, fast and slow. In both CA1 and CA3 neurones the fast component amplitude was preferentially sensitive to vitronectin, with its relatively larger contribution to total current in vitronectin-exposed cells contributing to the acceleration of I_h activation. Further, HCN1 immunoreactivity appeared elevated in vitronectin-exposed slices, while HCN2 levels appeared unaltered. We suggest that vitronectin-stimulated increases in I_h may potentially affect excitability under pathological conditions.

(Received 28 May 2004; accepted after revision 17 August 2004; first published online 19 August 2004)
Corresponding author M. E. Barish: Division of Neurosciences, Beckman Research Institute of the City of Hope, 1450 East Duarte Road, Duarte, CA 91010, USA. Email: mbarish{at}coh.org

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