Abstract
Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN channels and Ih current amplitudes are reduced in layer (L) 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with an increased EPSP temporal summation. Here, we examine the effects of HCN channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN channel antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.
Highlights
Synaptic excitation of L5 pyramidal cells is regulated by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels (Berger et al, 2001; Berger and Lüscher, 2003)
Rebound responses were virtually absent in both groups (Control: 0.14 mV ± 0.1, n = 10; Lesion: 0.32 mV ± 0.2, n = 7; data not shown). These results are consistent with decreased HCN channel functioning in L5 fast spiking cells in lesioned animals
We examined the role of HCN channels in regulating intrinsic and synaptic excitability of two classes of L5 interneurons in rat neocortex
Summary
Synaptic excitation of L5 pyramidal cells is regulated by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels (Berger et al, 2001; Berger and Lüscher, 2003). These channels mediate Ih, a non-inactivating, cationic current activated by membrane hyperpolarization (Robinson and Siegelbaum, 2003). Somatostatin (SOM)-expressing Martinotti cells are identified by ascending axon collaterals which reach L1 and ramify extensively (Kawaguchi and Kubota, 1997), can be sub-classified as regular spiking or burst firing (Wang et al, 2004; Uematsu et al, 2008), display spike frequency accommodation, mediate frequencydependent disynaptic inhibition (Silberberg and Markram, 2007) and target oblique, apical and tuft dendrites of L5 pyramidal cells (Berger et al, 2010)
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