Striatal cholinergic transmission. Focus on nicotinic receptors' influence in striatal circuits

Abstract

The critical role of acetylcholine (ACh) in the basal ganglia is evident from the effect of cholinergic agents in patients suffering from several related neurological disorders, such as Parkinson's disease, Tourette syndrome, or dystonia. The striatum possesses the highest density of ACh markers in the basal ganglia underlying the importance of ACh in this structure. Striatal cholinergic interneurons (CINs) are responsible for the bulk of striatal ACh, although extrinsic cholinergic afferents from brainstem structures may also play a role. CINs are tonically active, and synchronized pause in their activity occurs following the presentation of salient stimuli during behavioral conditioning. However, the synaptic mechanisms involved are not fully understood in this physiological response. ACh modulates striatal circuits by acting on muscarinic and nicotinic receptors existing in several combinations both presynaptically and postsynaptically. While the effects of ACh in the striatum through muscarinic receptors have received particular attention, nicotinic receptors function has been less studied. Here, after briefly reviewing relevant results regarding muscarinic receptors expression and function, I will focus on striatal nicotinic receptor expressed presynaptically on glutamatergic and dopaminergic afferents and postsynaptically on diverse striatal interneurons populations. I will also review recent evidence suggesting the involvement of different GABAergic sources in two distinct nicotinic-receptor-mediated striatal circuits: the disynaptic inhibition of striatal projection neurons and the recurrent inhibition among CINs. A better understanding of striatal nicotinic receptors expression and function may help to develop targeted pharmacological interventions to treat brain disorders such as Parkinson's disease, Tourette syndrome, dystonia, or nicotine addiction.

Keywords: GABAergic interneurons; acetylcholine; cholinergic interneurons; cognitive flexibility; dopamine; electrophysiology; glutamate; muscarinic receptors; nicotinic receptors.

Figure 1.. Nicotinic receptor expression in striatal circuits.

Schematic describing our current knowledge of nicotinic receptor (nAChRs) subtypes expression presynaptically on striatal afferents originating from the cortex, the parafascicular nucleus of the thalamus (PfN), dopaminergic neurons or brainstem cholinergic structures (pedunculopontine nucleus, PPN and laterodorsal tegmentum, LDT) as well as postsynaptically on striatal neurons. Note that while the majority of striatal interneurons express nicotinic receptors, spiny projection neurons (SPNs) do not seem to express any. Importantly, striatal GABAergic interneurons express various subtypes of nAChRs which may confer selective functions in striatal microcircuits discussed in this review. CINs: Cholinergic interneurons; NGF: Neurogliaform; FSI: Fast-spiking interneuron; LTS: Low threshold spike; SABI: Spontaneously active bursty interneuron; THIN: Tyrosine hydroxylase-expressing interneuron; FAI: Fast-adapting interneuron; CR: Calretinin-expressing interneurons.

Figure 2.. Nicotinic-mediated striatal GABAergic circuits.

So far, two distinct GABAergic striatal microcircuits involving β2-subunit containing nicotinic receptor (β2*-nAChR) have been described. Left. Optogenetic activation of striatal cholinergic interneurons (CINs) evoke a disynaptic composite IPSC in SPNs. This inhibition can be subdivided into a fast and a slow component. While the slow component is mediated by CINs activation of neurogliaform interneurons (NGF), the source of the fast IPSC is still under investigation. Right. Single CIN activation or optogenetic stimulation of populations of CINs induces polysynaptic recurrent inhibition among CINs which can participate in synchronizing CINs activity. Part of this inhibition involves nicotinic receptors activation on THINs, which are reciprocally connected with CINs. The contribution of other subtypes of striatal GABAergic interneurons or extrinsic GABAergic afferents is yet to discover.