Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex.

Wei Cai,Bao-Ming Li,Shu-Su Liu,Xue-Han Zhang

doi:10.1242/bio.058840

Abstract

ABSTRACTHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in neurons in the central nervous system. It has been documented that HCN channels regulate the intrinsic excitability of pyramidal cells in the medial prefrontal cortex (mPFC) of rodents. Here, we report that HCN channels limited GABAergic transmission onto pyramidal cells in rat mPFC. The pharmacological blockade of HCN channels resulted in a significant increase in the frequency of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs) in mPFC pyramidal cells, whereas potentiation of HCN channels reversely decreases the frequency of mIPSCs. Furthermore, such facilitation effect on mIPSC frequency required presynaptic Ca2+ influx. Immunofluorescence staining showed that HCN channels expressed in presynaptic GABAergic terminals, as well as in both soma and neurite of parvalbumin-expressing (PV-expressing) basket cells in mPFC. The present results indicate that HCN channels in GABAergic interneurons, most likely PV-expressing basket cells, constrain inhibitory control over layer 5–6 pyramidal cells by restricting presynaptic Ca2+ entry.

Highlights

Hyperpolarization activated cyclic nucleotide-gated (HCN) channels are richly expressed in the central nervous system, which consist of four either identical or nonidentical subunits (HCN1-4)[1], are activated with membrane hyperpolarization, and are regulated directly by cAMP [2,3,4]
We demonstrated that HCN channels are richly present in cells expressing parvalbumin, and the pharmacological blocking of HCN channels enhances GABA release onto pyramidal neurons in layers 5-6 of medial prefrontal cortex (mPFC) through increasing Ca2+ influx via T-type Ca2+ channels
The T-type Ca2+ channels are expressed in parvalbumin-expressing basket cells in the 5th and 6th cortical layers [48, 49], suggesting that HCN channels may provide a regulatory mechanism for controlling GABA releases from GABAergic terminals

Summary

Introduction

Hyperpolarization activated cyclic nucleotide-gated (HCN) channels are richly expressed in the central nervous system, which consist of four either identical or nonidentical subunits (HCN1-4)[1], are activated with membrane hyperpolarization, and are regulated directly by cAMP [2,3,4]. Somato-dendritic HCN channels in pyramidal neurons modulate spike firing and synaptic potential integration by influencing the membrane resistance and resting membrane potential[10]. In addition to their dendritic localization, HCN channels are expressed in cortical and hippocampal axons and synaptic terminals of inhibitory and excitatory neurons [5, 9, 11,12,13]. Presynaptic HCN current, Ih, has been indicated to affect excitatory synaptic transmission in invertebrate neurons and vertebrate neurons where Ih has been shown to influence excitatory transmitter release [14,15,16,17] via affecting the activities of presynaptic terminal Ca2+ channels [17]. Presynaptic Ih affects inhibitory neurotransmission in the rodent globus pallidus, cerebellum and hippocampus [12, 13, 18, 19], though the mechanism by which these occur is unknown

Methods

Results

Conclusion