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F69. MUSCARINIC M1 RECEPTOR SEQUENCE VARIATION AND GENERAL COGNITION

ABSTRACT: Abstract Background It has been reported that individuals with schizophrenia who are homozygous at the c.267C > A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor gene exhibit impaired Wisconsin Card Sorting Test (WCST) performance compared to those who are heterozygous. This investigation sought to examine the influence rs2067477 genotype variation has on general cognitive function. Methods 87 individuals with schizophrenia/schizoaffective disorder (Sz/SAD) and 224 healthy controls (HC) completed the MATRICS Consensus Cognitive Battery and D-KEFS Stroop to determine whether rs2067477 genotype variation influenced cognition. Results No significant differences in MCCB domain scores or D-KEFS Stroop were found across genotype in both a patient-only sample and a combined patient-healthy control sample Discussion Despite rs2067477 genotype variation being shown to influence executive functioning, specifically performance on the WCST in individual with schizophrenia, no such association could be detected across a number of general cognitive domains or on an alternative measure of shifting/cognitive flexibility.

SUBMITTER: Carruthers S

PROVIDER: S-EPMC5887375 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Project description:Aggregation of amyloid beta and loss of cholinergic innervation in the brain are predominant components of Alzheimer's disease pathology and likely underlie cognitive impairment. Acetylcholinesterase inhibitors are one of the few treatment options for Alzheimer's disease, where levels of available acetylcholine are enhanced to counteract the cholinergic loss. However, these inhibitors show limited clinical efficacy. One potential explanation for this is a concomitant dysregulation of cholinergic receptors themselves as a consequence of the amyloid beta pathology. We tested this hypothesis by examining levels of M1 muscarinic acetylcholine receptors in the temporal cortex from seven Alzheimer's disease and seven non-disease age-matched control brain tissue samples (control: 85 ± 2.63 years old, moderate Alzheimer's disease: 84 ± 2.32 years old, P-value = 0.721; eight female and six male patients). The samples were categorized into two groups: 'control' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'No Alzheimer's disease', and Braak staging pathology of I-II) and 'moderate Alzheimer's disease' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'possible/probable Alzheimer's disease', and Braak staging pathology of IV). We find that in comparison to age-matched controls, there is a loss of M1 muscarinic acetylcholine receptors in moderate Alzheimer's disease tissue (control: 2.17 ± 0.27 arbitrary units, n = 7, Mod-AD: 0.83 ± 0.16 arbitrary units, n = 7, two-tailed t-test, t = 4.248, P = 0.00113). Using a functional rat cortical brain slice model, we find that postsynaptic muscarinic acetylcholine receptor function is dysregulated by aberrant amyloid beta-mediated activation of metabotropic glutamate receptor 5. Crucially, blocking metabotropic glutamate receptor 5 restores muscarinic acetylcholine receptor function and object recognition memory in 5XFAD transgenic mice. This indicates that the amyloid beta-mediated activation of metabotropic glutamate receptor 5 negatively regulates muscarinic acetylcholine receptor and illustrates the importance of muscarinic acetylcholine receptors as a potential disease-modifying target in the moderate pathological stages of Alzheimer's disease.

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F69. MUSCARINIC M1 RECEPTOR SEQUENCE VARIATION AND GENERAL COGNITION

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