title: Direct and GABA-mediated indirect effects of nicotinic ACh receptor agonists on striatal neurones.
abstract: Choline acetyltransferase-expressing interneurones (ChAT)(+) of the striatum influence the activity of medium spiny projecting neurones (MSNs) and striatal output via a disynaptic mechanism that involves GABAergic neurotransmission. Using transgenic mice that allow visual identification of MSNs and distinct populations of GABAergic interneurones expressing neuropeptide Y (NPY)(+), parvalbumin (PV)(+) and tyrosine hydroxylase (TH)(+), we further elucidate this mechanism by studying nicotinic ACh receptor (nAChR)-mediated responses. First, we determined whether striatal neurones exhibit pharmacologically induced nicotinic responses by performing patch-clamp recordings. With high [Cl(-)](i), our results showed increased spontaneous IPSC frequency and amplitude in MSNs as well as in the majority of interneurones. However, direct nAChR-mediated activity was observed in interneurones but not MSNs. In recordings with physiological [Cl(-)](i), these responses manifested as inward currents in the presence of tetrodotoxin and bicuculline methobromide. Nicotinic responses in MSNs were primarily mediated through GABA(A) receptors in feedforward inhibition. To identify the GABAergic interneurones that mediate the response, we performed dual recordings from GABAergic interneurones and MSNs. Both TH(+) and neurogliaform subtypes of NPY(+) (NPY(+) NGF) interneurones form synaptic connections with MSNs, although the strength of connectivity, response kinetics and pharmacology differ between and within the two populations. Importantly, both cell types appear to contribute to nAChR-mediated GABAergic responses in MSNs. Our data offer insight into the striatal network activity under cholinergic control, and suggest that subclasses of recently identified TH(+) and NPY(+) interneurones are key mediators of striatal nicotinic responses via GABAergic tonic and phasic currents.
authors.affiliation: Department of Pharmacology and Physiology, Basic Science Building, Rm 225, Georgetown University School of Medicine, 3900 Reservoir Rd, Washington, DC 20007, USA.
authors.forename: Ruixi
authors.initials: R
authors.lastname: Luo
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Janssen
authors.forename: John G
authors.initials: JG
authors.lastname: Partridge
authors.forename: Stefano
authors.initials: S
authors.lastname: Vicini
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid