Recurrent Inhibitory Network among Striatal Cholinergic Interneurons

Abstract

The striatum plays a central role in sensorimotor learning and action selection. Tonically active cholinergic interneurons in the striatum give rise to dense axonal arborizations and significantly shape striatal output. However, it is not clear how the activity of these neurons is regulated within the striatal microcircuitry. In this study, using rat brain slices, we find that stimulation of intrastriatal cholinergic fibers evokes polysynaptic GABA A IPSCs in cholinergic interneurons. These polysynaptic GABA A IPSCs were abolished by general nicotinic acetylcholine receptor antagonists and also by a specific antagonist of nicotinic receptors containing ␤2 subunits. Dopamine receptor antagonists or dopamine depletion failed to block polysynaptic IPSCs, indicating that phasic dopamine release does not directly mediate the polysynaptic transmission. Dual recording from pairs of cholinergic interneurons revealed that activation of a single cholinergic interneuron is capable of eliciting polysynaptic GABA A IPSCs both in itself and in nearby cholinergic interneurons. Although polysynaptic transmission arising from a single cholinergic interneuron was depressed during repetitive 2 Hz firing, intrastriatal stimulation reliably evoked large polysynaptic IPSCs by recruiting many cholinergic fibers. We also show that polysynaptic GABAergic inhibition leads to a transient suppression of tonic cholinergic interneuron firing. We propose a novel microcircuit in the striatum, in which cholinergic interneurons are connected to one another through GABAergic interneurons. This may provide a mechanism to convert activation of cholinergic interneurons into widespread recurrent inhibition of these neurons via nicotinic excitation of striatal GABAergic neurons.

Subregion-specific modulation of excitatory input and dopaminergic output in the striatum by tonically activated glycine and GABAA receptors

“…Since striatal cholinergic interneurons drive excitation of surrounding GABAergic neurons (de Rover et al, 2002), activation of cholinergic interneurons could be converted into widespread recurrent inhibition via nicotinic excitation of GABAergic neurons (Sullivan et al, 2008). Involvement of both nicotinic and GABA A receptors in strychnine-mediated enhancement of excitatory input was also supported by our data showing that the increase in PS amplitude was inhibited by mecamylamine, picrotoxin, and bicuculline.…”

“…MSNs form a weak lateral inhibitory network among themselves via local axon collaterals (feedback inhibition), while feedforward inhibition by GABAergic interneurons appears to exert a more powerful control of striatal excitability (Tepper et al, 2004). The striatum also contains cholinergic interneurons, which have been implicated in controlling both glutamatergic and GABAergic transmission onto projecting MSNs (Zhou et al, 2002;Pakhotin and Bracci, 2007;Sullivan et al, 2008). Furthermore, strychnine-sensitive glycine…”

Dopamine-modulated dynamic cell assemblies generated by the GABAergic striatal microcircuit

“…The low-threshold spiking class correspond to the interneurons that co-express nitric oxide, somatostatin, and neuropeptide Y (Kawaguchi, 1993;Kawaguchi et al, 1995); this class may also express GABA (Kubota & Kawaguchi, 2000). The FSIs probably dominate MSN behaviour, as they form far more synapses on somas (Kubota & Kawaguchi, 2000), whereas the low-threshold spiking neurons may form an inhibitory network between the cholinergic interneurons (Sullivan et al, 2008).…”

Visual-Induced Excitation Leads to Firing Pauses in Striatal Cholinergic Interneurons

“…However, the effect of DA on CINs is depolarizing and causes sustained spike rate increases (Aosaki et al, 1998;Deng et al, 2007); therefore, phasic dopamine is unlikely to drive the pause directly. Second, CINs have recently been shown to inhibit their own activity by engaging an as-yet-unidentified population of GABAergic neurons (Sullivan et al, 2008). Strong intrastriatal stimulation was required to induce synchronized CIN firing and elicit this effect; how this mechanism is engaged in vivo and acquired through learning is yet to be determined.…”