M1 Muscarinic Acetylcholine Receptors Activate Extracellular Signal-Regulated Kinase in CA1 Pyramidal Neurons in Mouse Hippocampal Slices

Berkeley, Jennifer L.; Gomeza, Jesús; Wess, Jürgen; Hamilton, Susan; Nathanson, Neil M.; Levey, Aĺlan I.

doi:10.1006/mcne.2001.1042

Cited by 84 publications

(71 citation statements)

References 48 publications

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“…ERK activation has been shown to modulate APP processing and Aβ generation (24,25,36). M1 muscarinic acetylcholine receptors activate the ERK signaling pathway (37), which is at least in part responsible for their regulation of APP processing (38). Similar to our current data with serotonin, M1-mediated down-regulation of Aβ acts by increasing α-secretase cleavage of APP (8,9).…”

Section: Discussionsupporting

confidence: 80%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

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

314

307

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Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

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Section: Discussionsupporting

confidence: 80%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

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

314

307

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“…In addition to its in vitro evidence for muscarinic agonism, in vivo evidence comes from the fact that in rodents NDMC administration, but not clozapine, leads to a dose-dependent activation of mitogen-activated protein kinase (MAPK) in the CA 1 region of the hippocampus and also potentiates NDMA receptor currents, actions mediated by the muscarinic M 1 receptors (Berkeley et al, 2001;Sur et al, 2003;Weiner et al, 2004). In fact muscarinic agonists like xanomeline, BuTAC, and PTAC (which are relatively devoid of D 2 activity) have been shown to be very active in CAR (Bymaster et al, , 2002 and xanomeline has been shown to have antipsychotic and pro-cognitive efficacy in humans (Bodick et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Natesan

Reckless

Barlow

et al. 2006

Neuropsychopharmacol

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There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT 2 antagonist and as a partial agonist to dopamine D 2 and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D 2 and 5-HT 2 receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10-60 mg/kg/s.c.) showed high 5-HT 2 (64-79%), but minimal D 2 occupancy (o15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.

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“…In addition, the present changes in p-ERK1/2 levels within the hippocampus and the amygdala are unlikely to be attributable to changes in ERK1/2 expression. Indeed, previous immunohistochemical data or Western blot analyses systematically showed no change in ERK1/2 expression whatever the brain region considered (including both the hippocampus and the amygdala), the postconditioning delay, or the cholinergic manipulation used (Atkins et al, 1998;Rosenblum et al, 2000;Schafe et al, 2000;Berkeley et al, 2001).…”

Section: Ach Manipulation Affects Erk1/2 Activation In the Amygdalamentioning

confidence: 95%

“…Activation of ERK1/2 was studied because it is an important molecular marker commonly used to delineate learning-dependent circuits as a function of the prevalent conditioned association encoded. First, previous studies demonstrated that p-ERK1/2 can serve in neural cells, and particularly in hippocampal neurons, as convergence site for several neurotransmitter receptor activation, including acetylcholine receptors (Rosenblum et al, 2000;Berkeley et al, 2001). Second, ERK1/2 activation has been shown to be critically required for learning-dependent plasticity within the hippocampus and the amygdala, in contextual and tone CS fear conditioning, respectively (Atkins et al, 1998;Schafe et al, 2000;Shalin et al, 2004;Revest et al, 2005;Trifilieff et al, 2006).…”

Section: Ach Manipulation Affects Erk1/2 Activationmentioning

confidence: 99%

Extracellular Hippocampal Acetylcholine Level Controls Amygdala Function and Promotes Adaptive Conditioned Emotional Response

Calandreau¹,

Trifilieff²,

Mons³

et al. 2006

J. Neurosci.

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Ample data indicate that tone and contextual fear conditioning differentially require the amygdala and the hippocampus. However, mechanisms subserving the adaptive selection among environmental stimuli (discrete tone vs context) of those that best predict an aversive event are still elusive. Because the hippocampal cholinergic neurotransmission is thought to play a critical role in the coordination between different memory systems leading to the selection of appropriate behavioral strategies, we hypothesized that this cholinergic signal may control the competing acquisition of amygdala-mediated tone and contextual conditioning. Using pavlovian fear conditioning in mice, we first show a higher level of hippocampal acetylcholine release and a specific pattern of extracellular signalregulated kinase 1/2 (ERK1/2) activation within the lateral (LA) and basolateral (BLA) amygdala under conditions in which the context is a better predictor than a discrete tone stimulus. Second, we demonstrate that levels of hippocampal cholinergic neurotransmission are causally related to the patterns of ERK1/2 activation in amygdala nuclei and actually determine the selection among the context or the simple tone the stimulus that best predicts the aversive event. Specifically, decreasing the hippocampal cholinergic signal not only impaired contextual conditioning but also mimicked conditioning to the discrete tone, both in terms of the behavioral outcome and the LA/BLA ERK1/2 activation pattern. Conversely, increasing this cholinergic signal not only disrupted tone conditioning but also promoted contextual fear conditioning. Hence, these findings highlight that hippocampal cholinergic neurotransmission controls amygdala function, thereby leading to the selection of relevant emotional information.

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M1 Muscarinic Acetylcholine Receptors Activate Extracellular Signal-Regulated Kinase in CA1 Pyramidal Neurons in Mouse Hippocampal Slices

Cited by 84 publications

References 48 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Evaluation of N-Desmethylclozapine as a Potential Antipsychotic—Preclinical Studies

Extracellular Hippocampal Acetylcholine Level Controls Amygdala Function and Promotes Adaptive Conditioned Emotional Response

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