Widespread decreases in cortical muscarinic receptors in a subset of people with schizophrenia

Gibbons, Andrew S.; Scarr, Elizabeth; Boer, Simone; Money, Tammie; Jeon, Wonjin; Felder, Christian C.; Dean, Brian

doi:10.1017/s1461145712000028

Cited by 57 publications

(54 citation statements)

References 49 publications

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“…The present findings are especially interesting in light of multiple previous studies that cholinergic signaling Role of M 1 PAM in PCP-treated mice A Ghoshal et al is disrupted in the PFC and other cortical and limbic forebrain regions of schizophrenia patients (Berman et al, 2007;Dean et al, 2002;Raedler et al, 2007;Scarr et al, 2009a;Zavitsanou et al, 2004). Of particular interest is the recent finding that a defined subset of schizophrenia patients display decreases in M 1 levels in PFC and other cortical and forebrain regions (Dean et al, 2002;Gibbons et al, 2013). Interestingly, studies using brain autopsies from a broad range of schizophrenia patients show reduced methylation of the promoter for the gene encoding the M 1 mAChR subtype that may contribute to the reduced M 1 expression in their brain .…”

Section: Role Of M 1 Pam In Pcp-treated Micesupporting

confidence: 53%

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

Ghoshal

Rook

Dickerson

et al. 2015

Neuropsychopharmacol

122

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Schizophrenia patients exhibit deficits in signaling of the M 1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M 1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M 1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M 1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M 1 PAMs as a novel approach for the treatment of schizophrenia.

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Section: Role Of M 1 Pam In Pcp-treated Micesupporting

confidence: 53%

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

Ghoshal

Rook

Dickerson

et al. 2015

Neuropsychopharmacol

122

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“…Studies comparing M1 and M4 muscarinic receptor density across diagnosis groups identified reductions in patients with schizophrenia, but not in bipolar disorder or major depression (Gibbons et al, 2009; Zavitsanou et al, 2004). Antipsychotic medication use or dose does not appear related to decreased muscarinic receptor density (Crook et al, 2001, 2000, 1999; Dean et al, 2002; Deng and Huang, 2005; Gibbons et al, 2013, 2009; Zavitsanou et al, 2004). Given the already decreased central cholinergic activity through fewer muscarinic receptors in schizophrenia patients, even a small amount of anticholinergic load may cause a significant adverse impact on cognition due to M1 receptor saturation, which may in turn make them more vulnerable to cognitive impairing effects of anticholinergic medication burden compared to those with mood-related psychotic disorders or healthy controls who have greater M1 availability (Tani et al, 2015).…”

Section: Discussionmentioning

confidence: 91%

“…Numerous post-mortem studies measuring M1/M4 selective radio-ligand binding (i.e. [ 3 H]pirenzepine) (Crook et al, 2001, 2000, 1999; Dean et al, 2002, 1996; Deng and Huang, 2005; Gibbons et al, 2013; Zavitsanou et al, 2004), as well as the levels of protein and mRNA (Dean et al, 2002; Mancama et al, 2003), have observed a widespread reduction of muscarinic receptors, notably M1, in postmortem brain samples of schizophrenia patients. Additionally, in vivo analyses identified a 20–35% decrease of muscarinic receptor availability in multiple brain regions in unmedicated patients with schizophrenia compared to the healthy controls (Raedler et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Cognitive burden of anticholinergic medications in psychotic disorders

Eum

Hill

Rubin

et al. 2017

Schizophrenia Research

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Background Patients with psychotic disorders are often treated with numerous medications, many of which have anticholinergic activity. We assessed cognition in relation to the cumulative anticholinergic burden of multiple drugs included in treatment regimens of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Method Clinically stable participants with schizophrenia (n=206), schizoaffective disorder (n=131), and psychotic bipolar disorder (n=146) were examined. Anticholinergic properties of all scheduled drugs were quantified using the Anticholinergic Drug Scale (ADS). ADS scores were summed across individual drugs to create a total ADS burden score for each participant and examined in relation to the Brief Assessment of Cognition in Schizophrenia (BACS). Results Anticholinergic burden aggregated across all medications was inversely related to cognitive performance starting at ADS scores of 4 in participants with schizophrenia. Those with ADS scores ≥4 had lower composite BACS scores compared to those with ADS<4 (p=0.004). Among BACS subtests, Verbal Memory was the most adversely affected by high anticholinergic burden. Despite similar anticholinergic burden scores across groups, a significant effect of anticholinergic burden was not detected in schizoaffective or psychotic bipolar disorder. Conclusion We identified an adverse effect threshold of anticholinergic burden on cognition in clinically stable participants with schizophrenia. This relationship was not identified in affective psychoses. Examination of other medications, doses, and clinical measures did not account for these findings. Patients with schizophrenia may have increased cognitive susceptibility to anticholinergic medications and the aggregate effects of one’s medication regimen may be important to consider in clinical practice.

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“…We have shown that, under the assay conditions we use, [ 3 H] pirenzepine predominately binds to the CHRM1 Gibbons et al, 2013). Importantly, clinical and preclinical studies suggest that cortical CHRM1 is important in cognitive functions (Anagnostaras et al, 2003;Nathan et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

An investigation of the factors that regulate muscarinic receptor expression in schizophrenia

Seo

Scarr

Dean

2014

Schizophrenia Research

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We previously identified a group of subjects with schizophrenia who, on average, have a 75% decrease in cholinergic receptor, muscarinic 1 (CHRM1) in Brodmann's area (BA) 9. To extend this finding, we determined i) if the decrease in CHRM1 was present in another functionally related CNS region (BA6), ii) whether the marked decrease in CHRM1 was accompanied by changes in levels of other CHRMs and iii) potential factors responsible for the decreased CHRM1 expression. We measured CHRM1 and CHRM3 using in situ radioligand binding with [(3)H]pirenzepine and [(3)H]4-DAMP respectively in BA6 from 20 subjects with schizophrenia who had low levels of CHRM1 in BA9 (SzLow[(3)H]PZP), 18 subjects with schizophrenia whose levels of CHRM1 were similar to controls (SzNormal[(3)H]PZP) and 20 control subjects. Levels of CHRM1, 3 and 4 mRNA were measured using qPCR and levels of the transcription factors, SP1 and SP3, were determined using Western blots. In BA6, the density of [(3)H]pirenzepine binding was decreased in subjects with SzLow[(3)H]PZP (p<0.001) compared to controls. The density of [(3)H]4-DAMP binding, levels of CHRM1, 3 and 4 mRNA and levels of SP1 and SP3 was not significantly different between the three groups. This study shows that the previously identified decrease in CHRM1 expression is not confined to the dorsolateral prefrontal cortex but is present in other cortical areas. The effect shows some specificity to CHRM1, with no change in levels of binding to CHRM3. Furthermore, this decrease in CHRM1 does not appear to be associated with low levels of CHRM1 mRNA or to simply be regulated by the transcription factors, SP1 and SP3, suggesting that other mechanisms are responsible for the decreased CHRM1 in these subjects.

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Widespread decreases in cortical muscarinic receptors in a subset of people with schizophrenia

Cited by 57 publications

References 49 publications

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

Potentiation of M1 Muscarinic Receptor Reverses Plasticity Deficits and Negative and Cognitive Symptoms in a Schizophrenia Mouse Model

Cognitive burden of anticholinergic medications in psychotic disorders

An investigation of the factors that regulate muscarinic receptor expression in schizophrenia

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