Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum

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 M₄ or double M₂/M₄ 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 M₄^-/- and abolished in M₂/M₄^-/- mice, suggesting an involvement of both M₂ and M₄ autoreceptors. In MSNs from both M ₄^-/- and M₂/M₄^-/- mice, muscarine caused a membrane depolarization that was prevented by the M ₁ receptor-preferring antagonist pirenzepine (100 nM), suggesting that M₁ 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 M₄^-/- and M₂/M₄^-/- mice, as well as in wild-type mice pretreated with the M ₂/M₄ 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 μM), 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 M₂/M ₄ muscarinic autoreceptors regulate ACh release from striatal ChIs. As a consequence, endogenous ACh drives the polarity of bidirectional synaptic plasticity.