Cell Type-Specific Properties of Subicular GABAergic Currents Shape Hippocampal Output Firing Mode

Abstract

GABAergic function of the subiculum is central to the regulation of hippocampal output activity. Subicular neuronal networks are indeed under potent control by local inhibition. However, information about the properties of GABAergic currents generated by neurons of this parahippocampal area in normal tissue is still missing. Here, we describe GABAA receptor (GABAAR)-mediated phasic and tonic currents generated by principal cells (PCs) and interneurons (INs) of the rat subiculum. We show that in spite of similar synaptic current densities, INs generate spontaneous IPSCs (sIPSCs) that occur less frequently and exhibit smaller charge transfer, thus receiving less synaptic total current than PCs. Further distinction of PCs between intrinsically bursting (IB) and regular-spiking (RS) neurons suggested that sIPSCs generated by the two PC sub-types are likely to be similar. PCs and INs are also controlled by a similar tonic inhibition. However, whereas a comparable tonic current density is found in RS cells and INs, IB neurons are constrained by a greater inhibitory tone. Finally, pharmacological blockade of GABAAR did not promote functional switch of RS neurons to IB mode, but influenced the bursting propensity of IB cells and released fast spiking activity in INs. Our findings reveal differences in GABAergic currents between PCs and INs as well as within PC sub-types. We propose that GABAergic inhibition may shape hippocampal output activity by providing cell type-specific fine-tuning of subicular excitatory and inhibitory drives.

Depolarized GABAergic Signaling in Subicular Microcircuits Mediates Generalized Seizure in Temporal Lobe Epilepsy

“…We previously reported that low-frequency stimulation targeting the subiculum alleviates sGS in the kindling and pilocarpine models (Zhong et al, 2012); it is therefore highly likely that the subiculum may serve as the ''choke point'' (Paz and Huguenard, 2015) for synchronous firing spreading from the hippocampus during sGS and play an important role in the control of sGS. The role of the subiculum in gating hippocampal output is largely contributed by its intrinsic microcircuits (Behr et al, 2009;Panuccio et al, 2012); that is, local GABAergic signaling reduces the propagation of afferent excitation and modulates the firing behavior of subicular pyramidal neurons. Although degeneration of various inhibitory interneuron populations in the subiculum has been shown in TLE (de Guzman et al, 2006;Knopp et al, 2008), the role of the subiculum with cellular precision in causal underpinnings of sGS in TLE has not yet been investigated due to the lack of a specific approach.…”

Tonic current through GABAA receptors and hyperpolarization‐activated cyclic nucleotide‐gated channels modulate resonance properties of rat subicular pyramidal neurons

“…We aimed to isolate the tonic component of inhibition from the synaptic component in subicular pyramidal neurons using GABA A receptor antagonists. To this effect, we used a non‐competitive antagonist (picrotoxin) and competitive antagonist (gabazine) (Chandra et al ., ; Curia et al ., ; Panuccio et al ., ). Application of picrotoxin (100 μ m ) to slices revealed an outward shift of the holding current along with blockade of phasic currents ( n = 7, Fig.…”

“…Additionally, GABA can activate a distinct pool of extrasynaptic GABA A receptors to mediate a persistent ‘tonic’ form of inhibition. Picrotoxin‐sensitive tonic currents were recorded in subicular pyramidal neurons in acute rat hippocampal brain slices, consistent with previous reports of a tonic GABA A receptor‐mediated conductance in subicular pyramidal neurons (Panuccio et al ., ). The two major subunits involved in tonic GABA A currents in the hippocampus are α5 and δ subunits.…”

“…The extrasynaptic high‐affinity GABA A receptors generally include a δ subunit (Stell et al ., ; Mtchedlishvili & Kapur, ) or α5 subunit in hippocampal neurons (Caraiscos et al ., ; Glykys & Mody, ). Somatic whole‐cell patch‐clamp recordings from subicular excitatory and inhibitory neurons revealed the presence of phasic and tonic inhibition (Biagini et al ., ; Panuccio et al ., ). Semi‐quantitative polymerase chain reaction and western blot experiments using whole subiculum showed the presence of α5 and δ subunits (Curia et al ., ).…”

Transition in subicular burst firing neurons from epileptiform activity to suppressed state by feedforward inhibition

“…During the late phase, intensive phasic GABAergic inhibition (IPSPs) leading to the suppression of epileptiform activity was observed as shown in Figs . Tonic inhibition through the activation of extrasynaptic GABAergic receptors has been reported in the subiculum (Curia et al ., ; Panuccio et al ., ). The intensive γ‐aminobutyric acid (GABA) release at the inhibitory synapses may increase the spillover of GABA leading to additional inhibition of the post‐synaptic neurons through tonic inhibition.…”