Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum.
Bonsi, Paola ; Martella, Giuseppina ; Cuomo, Dario ; et al. ; - ASI Sponsor
Jun - 2008
ISSN : 1529-2401 ;
journal : The Journal of neuroscience : the official journal of the Society for Neuroscience

Issue : 24
type: Article Journal

Abstract
Muscarinic autoreceptors regulate cholinergic tone in the striatum. We investigated the functional consequences of genetic deletion of striatal muscarinic autoreceptors by means of electrophysiological recordings from either medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) in slices from single M(4) or double M(2)/M(4) muscarinic acetylcholine receptor (mAChR) knock-out (-/-) mice. In control ChIs, the muscarinic agonist oxotremorine (300 nM) produced a self-inhibitory outward current that was mostly reduced in M(4)(-/-) and abolished in M(2)/M(4)(-/-) mice, suggesting an involvement of both M(2) and M(4) autoreceptors. In MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, muscarine caused a membrane depolarization that was prevented by the M(1) receptor-preferring antagonist pirenzepine (100 nM), suggesting that M(1) receptor function was unaltered. Acetylcholine has been involved in striatal long-term potentiation (LTP) or long-term depression (LTD) induction. Loss of muscarinic autoreceptor function is predicted to affect synaptic plasticity by modifying striatal cholinergic tone. Indeed, high-frequency stimulation of glutamatergic afferents failed to induce LTD in MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, as well as in wild-type mice pretreated with the M(2)/M(4) antagonist AF-DX384 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,1 1-dihydro-6H-pyrido[2,3b][1,4] benzodiazepin-6-one). Interestingly, LTD could be restored by either pirenzepine (100 nM) or hemicholinium-3 (10 microM), a depletor of endogenous ACh. Conversely, LTP induction did not show any difference among the three mouse strains and was prevented by pirenzepine. These results demonstrate that M(2)/M(4) muscarinic autoreceptors regulate ACh release from striatal ChIs. As a consequence, endogenous ACh drives the polarity of bidirectional synaptic plasticity.

keywords : Acetylcholine,Acetylcholine: metabolism,Animals,Autoreceptors,Autoreceptors: deficiency,Corpus Striatum,Corpus Striatum: cytology,Dose-Response Relationship,Electric Stimulation,Electric Stimulation: methods,Knockout,Long-Term Potentiation,Long-Term Potentiation: drug effects,Long-Term Potentiation: genetics,Long-Term Potentiation: radiation effects,Long-Term Synaptic Depression,Long-Term Synaptic Depression: drug effects,Long-Term Synaptic Depression: genetics,Long-Term Synaptic Depression: radiation effects,Mice,Muscarinic Antagonists,Muscarinic Antagonists: pharmacology,Muscarinic M2,Muscarinic M2: deficiency,Muscarinic M4,Muscarinic M4: deficiency,Neurons,Neurons: drug effects,Neurons: physiology,Neurons: radiation effects,Patch-Clamp Techniques,Patch-Clamp Techniques: methods,Radiation,Receptor