State-dependent GABAergic regulation of striatal spiny projection neuron excitability

Abstract

Synaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at sub-threshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. Activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in perforated patch recordings from both juvenile and adult SPNs. Molecular profiling of SPNs suggested that this relatively positive reversal potential was not attributable to NKCC1 expression, but rather to a dynamic equilibrium between KCC2 and Cl-/HCO3- cotransporters. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to coincident glutamatergic input. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation of the role intrastriatal GABAergic circuits.

The roles of surround inhibition for the intrinsic function of the striatum, analyzed in silico

“…The results clearly imply that when the starting point of the initiated plateau response is below the chloride equilibrium potential for GABA (set to −65 mV), the GABA input will initially provide a depolarization that can facilitate the plateau response, but if it starts above the equilibrium potential, it will instead reduce the amplitude. This excitatory effect of GABA has previously been observed ( 22 , 23 ). May et al ( 23 ) demonstrated that optogenetic and GABA uncaging led to depolarization in SPNs.…”

“…This excitatory effect of GABA has previously been observed ( 22 , 23 ). May et al ( 23 ) demonstrated that optogenetic and GABA uncaging led to depolarization in SPNs.…”