Cholinergic modulation of striatal microcircuits

Abstract

The purpose of this review is to bridge the gap between earlier literature on striatal cholinergic interneurons and mechanisms of microcircuit interaction demonstrated with the use of newly available tools. It is well known that the main source of the high level of acetylcholine in the striatum, compared to other brain regions, is the cholinergic interneurons. These interneurons provide an extensive local innervation that suggests they may be a key modulator of striatal microcircuits. Supporting this idea requires the consideration of functional properties of these interneurons, their influence on medium spiny neurons, other interneurons, and interactions with other synaptic regulators. Here, we underline the effects of intrastriatal and extrastriatal afferents onto cholinergic interneurons and discuss the activation of pre- and postsynaptic muscarinic and nicotinic receptors that participate in the modulation of intrastriatal neuronal interactions. We further address recent findings about corelease of other transmitters in cholinergic interneurons and actions of these interneurons in striosome and matrix compartments. In addition, we summarize recent evidence on acetylcholine-mediated striatal synaptic plasticity and propose roles for cholinergic interneurons in normal striatal physiology. A short examination of their role in neurological disorders such as Parkinson's, Huntington's, and Tourette's pathologies and dystonia is also included.

Keywords: acetylcholine; cholinergic interneurons; neuromodulation; striatum.

Figure 1

Connectivity of cholinergic interneurons in striatal microcircuits. Afferents from thalamus and cortex initiate direct glutamate‐induced postsynaptic activity in cholinergic and GABAergic interneurons (TH, PLTS, NPY‐NGF, FS subtypes) and in MSNs. ChI connectivity is reciprocal with other ChIs, PLTS, NPY‐NGF interneurons and with MSNs. Unidirectional connections from ChIs are to FA. Intrastriatal unidentified GABAergic terminals are contacted by ChIs expressing nicotinic and muscarinic receptors. These terminals could be dopaminergic (see Corelease in ChIs) or GABAergic arkypallidal (Extrastriatal: GABAergic). Synaptic connections between ChIs and FS are weak at best and probably FS to ChI connectivity does not exist. Reciprocal connectivity of MSNs with other MSNs and TH interneurons is also illustrated. For simplicity, only the dopaminergic input from SNc to ChIs is illustrated. Abbreviations of interneurons: ChI—cholinergic; PLTS—persistent low‐threshold spiking; NPY‐NGF—neuropeptide‐Y expressing neurogliaform; FA—fast adapting; FS—fast spiking, TH—tyrosine‐hydroxylase. See Table 1 for the numbers associated to connections.

Figure 2

Influence of afferents on cholinergic activity and release. As mentioned in the text, pre‐ and postsynaptic auto‐ and heteroreceptors to ChIs and their afferents can selectively affect the spatial and temporal release of ACh with important functional consequences. The participation of different types of glutamate receptors not only modulates ChI activity and ACh release but also exerts a fine control over dopamine release and other interneuronal and MSN activity. Coincident afferent striatal activation can induce short‐ and long‐term changes in ACh release important in the expression of striatal functions; in this way, ChIs, although few in number, are centrally positioned to likely control neuronal activity using wired and volume transmission. See Table 2 for the letters associated to the references of postsynaptic and presynaptic auto‐ and heteroreceptors.

Figure 3

Presynaptic muscarinic and nicotinic control of striatal glutamate release. Illustrated are the effects of ACh release within striatal microcircuits as discussed in the sections ‘dopaminergic terminals’ and ‘glutamatergic terminals’. The cartoon depicts Right: An increase in glutamate release mediated by presynaptic α7 nAChR on glutamate terminals. Left: A decrease in glutamate release mediated by two mechanisms: (i) a direct effect of ACh on presynaptic mAChRs (M₂, M₃, and M₄), or (ii) an indirect effect of ACh mediated by an increase in dopamine due to activation of α4β2* nAChRs on dopamine terminals. Dopamine action on inhibitory D₂ receptors on glutamate terminals reduces glutamate release. Such a complex action on the same terminal as depicted in (Fig. 2) [if indeed the receptors are coexpressed on single terminals] suggests either that fine control of the concentration of glutamate or the precise timing of it is important for MSN activity. The second, more indirect, inhibition by α4β2* nAChRs on dopamine terminals may be an important source of the increased activity in striatum in the absence of dopamine when such inhibition would be removed. The symbol code depicts the receptor types and their location.