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

Paola Bonsi, Giuseppina Martella, Dario Cuomo, Paola Platania, Giuseppe Sciamanna, Giorgio Bernardi, Jürgen Wess, Antonio Pisani

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)6258-6263
Number of pages6
JournalJournal of Neuroscience
Issue number24
Publication statusPublished - Jun 11 2008


  • Cholinergic interneuron
  • Electrophysiology
  • Long-term depression
  • Long-term potentiation
  • Muscarine
  • Striatal slices

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)


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