Loss of Muscarinic Autoreceptor Function Impairs Long-Term Depression But Not Long-Term Potentiation in the Striatum

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

doi:10.1523/jneurosci.1678-08.2008

Cited by 82 publications

(82 citation statements)

References 34 publications

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“…Previous reports have shown that endogenous acetylcholine can either modulate levels of synaptic plasticity or play a cooperative role with other receptors, such as NMDARs and mGluRs, so that LTD relies on activation of a combination of receptors (Kirkwood et al, 1999;Huber et al, 2001;Huang and Hsu, 2010). In contrast, very few reports show that a muscarinic antagonist alone can block activity-dependent LTD (Bonsi et al, 2008). Our results indicate that activation of mAChRs, by endogenous acetylcholine, is sufficient to induce LTD in mPFC.…”

Section: Activity-dependent Ltdmentioning

confidence: 46%

Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex

Caruana¹,

Warburton²,

Bashir³

2011

J. Neurosci.

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The medial prefrontal cortex (mPFC) forms part of a neural circuit involved in the formation of lasting associations between objects and places. Cholinergic inputs from the basal forebrain innervate the mPFC and may modulate synaptic processes required for the formation of object-in-place memories. To investigate whether acetylcholine regulates synaptic function in the rat mPFC, whole-cell voltage-clamp recordings were made from pyramidal neurons in layer V. Bath application of the cholinergic agonist carbachol caused a potent and long-term depression (LTD) of synaptic responses that was blocked by the muscarinic receptor antagonist scopolamine and was mimicked, in part, by the M 1 receptor agonists McN-A-343 or AF102B. Furthermore, inhibition of PKC blocked carbachol-mediated LTD. We next determined the requirements for activity-dependent LTD in the prefrontal cortex. Synaptic stimulation that was subthreshold for producing LTD did, however, result in LTD when acetylcholine levels were enhanced by inhibition of acetylcholinesterase or when delivered in the presence of the M 1 -selective positive allosteric modulator BQCA. Increasing the levels of synaptic stimulation resulted in M 1 receptor-dependent LTD without the need for pharmacological manipulation of acetylcholine levels. These results show that synaptic stimulation of muscarinic receptors alone can be critical for plastic changes in excitatory synaptic transmission in the mPFC. In turn, these muscarinic mediated events may be important in the formation of object-in-place memories. A loss of basal forebrain cholinergic neurons is a classic hallmark of Alzheimer's dementia and our results provide a potential explanation for the loss of memory associated with the disease.

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Section: Activity-dependent Ltdmentioning

confidence: 46%

Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex

Caruana¹,

Warburton²,

Bashir³

2011

J. Neurosci.

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“…Among the five subtypes of muscarinic receptors, MSNs predominantly express M1 and M4 receptors (43). Striatal synaptic plasticity is dependent upon endogenous ACh acting specifically on M1 receptors, with high levels of ACh facilitating long-term potentiation and lower levels facilitating longterm depression (44). Long-term potentiation has been associated with dyskinetic behavior in animal models of PD (45).…”

Section: Discussionmentioning

confidence: 99%

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Ding¹,

Won²,

Britt

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

173

192

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Treatment of Parkinson disease (PD) with L-3,4-dihydroxyphenylalanine (L-DOPA) dramatically relieves associated motor deficits, but L-DOPA-induced dyskinesias (LID) limit the therapeutic benefit over time. Previous investigations have noted changes in striatal medium spiny neurons, including abnormal activation of extracellular signal-regulated kinase1/2 (ERK). Using two PD models, the traditional 6-hydroxydopamine toxic lesion and a genetic model with nigrostriatal dopaminergic deficits, we found that acute dopamine challenge induces ERK activation in medium spiny neurons in denervated striatum. After repeated L-DOPA treatment, however, ERK activation diminishes in medium spiny neurons and increases in striatal cholinergic interneurons. ERK activation leads to enhanced basal firing rate and stronger excitatory responses to dopamine in striatal cholinergic neurons. Pharmacological blockers of ERK activation inhibit L-DOPA-induced changes in ERK phosphorylation, neuronal excitability, and the behavioral manifestation of LID. In addition, a muscarinic receptor antagonist reduces LID. These data indicate that increased dopamine sensitivity of striatal cholinergic neurons contributes to the expression of LID, which suggests novel therapeutic targets for LID.antagonist D opaminergic drugs are effective treatments for the motor symptoms of Parkinson disease (PD), but long-term therapy is limited by disabling abnormal involuntary movements, referred to as L-DOPA-induced dyskinesias (LID) (1). Thus, understanding the molecular and cellular mechanisms underlying LID will help identify more effective treatments for PD, and may also help elucidate the role of dopamine (DA) signaling in motor control.Several biochemical markers of LID have been studied in striatum using animal models. FosB/δFosB expression show a long-term temporal correlation with LID development in DA denervation PD models (2). The increased FosB expression persists over days or weeks and may contribute to the development of LID, but does not correlate with the L-DOPA-induced episodes of dyskinesia that follow each dose. To mediate expression of LID directly, cell signals should grow stronger with repeated L-DOPA treatment and show temporal correlation with acute dopaminergic stimulation. Acute administration of L-DOPA or dopamine agonists activates ERK1/2 by phosphorylation in striatal neurons of DA-denervated animals (3-7). In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions, coadministration of inhibitors of ERK1/2 phosphorylation during repeated L-DOPA treatments reduce LID development (4,8). Studies on these molecular changes have focused on the predominant cell type in the striatum, medium spiny neurons (MSN). In addition, although the unilateral 6-OHDA lesion has been the standard model for the PD phenotype, and particularly for LID, the abrupt nature of the lesion and extreme depletion of dopaminergic afferents has posed limitations in behavioral and biochemical studies.In this study, we used both a unilateral 6-OHDA lesion model and a g...

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“…However, autoinhibition of acetylcholine release is mediated primarily by M2R in hippocampus and cerebral cortex, but by M4R in striatum (Zhang et al 2002). Others report that both M2R and M4R autoreceptors modulate acetylcholine release from striatal cholinergic interneurons (Bonsi et al 2008). Activation of presynaptic M2Rs also promotes acetylcholine release from laterodorsal tegmental (LDT) and pedunculopontine (PPT) terminals (Baghdoyan et al 1998;Coleman et al 2004;Lydic and Baghdoyan 1993;Mitani et al 1988;Stenberg 2007) and modulates acetylcholine release and EEG slow waves and spindles in prefrontal cortex of mice (Douglas et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4

2010

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Loss of Muscarinic Autoreceptor Function Impairs Long-Term Depression But Not Long-Term Potentiation in the Striatum

Cited by 82 publications

References 34 publications

Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex

Induction of Activity-Dependent LTD Requires Muscarinic Receptor Activation in Medial Prefrontal Cortex

Enhanced striatal cholinergic neuronal activity mediatesl-DOPA–induced dyskinesia in parkinsonian mice

Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4

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