Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K(+) channels and Ih.

Sidney B Williams,John J Hablitz

doi:10.3389/fncel.2015.00089

Abstract

GABAergic interneurons provide the main source of inhibition in the neocortex and are important in regulating neocortical network activity. In the presence 4-aminopyridine (4-AP), CNQX, and D-APV, large amplitude GABAA-receptor mediated depolarizing responses were observed in the neocortex. GABAergic networks are comprised of several types of interneurons, each with its own protein expression pattern, firing properties, and inhibitory role in network activity. Voltage-gated ion channels, especially A-type K+ channels, differentially regulate passive membrane properties, action potential (AP) waveform, and repetitive firing properties in interneurons depending on their composition and localization. HCN channels are known modulators of pyramidal cell intrinsic excitability and excitatory network activity. Little information is available regarding how HCN channels functionally modulate excitability of individual interneurons and inhibitory networks. In this study, we examined the effect of 4-AP on intrinsic excitability of fast-spiking basket cells (FS-BCs) and Martinotti cells (MCs). 4-AP increased the duration of APs in both FS-BCs and MCs. The repetitive firing properties of MCs were differentially affected compared to FS-BCs. We also examined the effect of Ih inhibition on synchronous GABAergic depolarizations and synaptic integration of depolarizing IPSPs. ZD 7288 enhanced the amplitude and area of evoked GABAergic responses in both cell types. Similarly, the frequency and area of spontaneous GABAergic depolarizations in both FS-BCs and MCs were increased in presence of ZD 7288. Synaptic integration of IPSPs in MCs was significantly enhanced, but remained unaltered in FS-BCs. These results indicate that 4-AP differentially alters the firing properties of interneurons, suggesting MCs and FS-BCs may have unique roles in GABAergic network synchronization. Enhancement of GABAergic network synchronization by ZD 7288 suggests that HCN channels attenuate inhibitory network activity.

Highlights

GABAergic interneurons are the main source of inhibition in the neocortex and regulate the output of neocortical networks
We examined the influence of A-type K+ channels on action potential (AP) and repetitive firing properties of L2/3 fast-spiking basket cells (FS-BCs) and Martinotti cells (MCs) in the 4-AP model of interneuron network synchronization
Ih inhibition was accompanied by a increased late depolarization and associated with evoked depolarizing GABAergic responses (Control: 2314 ± 1276 mV∗ s, ZD: 4354 ± 1671 mV∗ s; t-test, p = 0.05; Figure 11F). These results suggest that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels differentially modulate synaptic integration of depolarizing IPSPs in MCs compared to FS-BCs

Summary

Introduction

GABAergic interneurons are the main source of inhibition in the neocortex and regulate the output of neocortical networks. During the early postnatal period, GABAA receptor mediated responses can be depolarizing due to a lack of KCC2, a K+-Cl− co-transporter that extrudes Cl− (Ben-Ari et al, 1989; Rivera et al, 1999) These depolarizing responses are involved in network synchronization during development (Khazipov et al, 1997; Allene et al, 2008). Application of the A-type K+ channel blocker 4-aminopyridine (4-AP) results in generation of a GABAergic, long-lasting depolarization (termed giant depolarizing potentials; Avoli and Perreault, 1987; Avoli et al, 1988) These responses persist when excitatory glutamatergic transmission is blocked with CNQX and D-APV (Aram et al, 1991; Michelson and Wong, 1991; Avoli et al, 1994; Benardo, 1997). The present study examines activity in specific classes of neocortical interneurons during such depolarizing events

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