A functional genetic variation of the 5-HT2a receptor affects human memory

Quervain, Dominique J.‐F. de; Henke, Katharina; Aerni, Amanda; Coluccia, Daniel; Wollmer, M. Axel; Höck, Christoph; Nitsch, Roger M.; Papassotiropoulos, Andreas

doi:10.1038/nn1146

Cited by 129 publications

(88 citation statements)

References 9 publications

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“…5 These comprise the adrenergic receptor 2A, catechol-O-methyltransferase, dopamine receptor D2, cholinergic muscarinic 2 receptor, brain-derived neurotrophic factor, metabotrophic glutamate receptor 3 and the serotonin receptor 2A. [6][7][8][9][10][11][12][13] To date only the apolipoprotein E e4 allele has been associated with cognitive decline in nondemented individuals and this finding has been challenged. [14][15][16][17][18][19] Serotonin has been shown to play a role in brain development and cognitive functioning.…”

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confidence: 99%

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

et al. 2005

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Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P ¼ 0.002, AH2 P ¼ 0.014), the test of semantic memory (P ¼ 0.010) and general cognitive ability (P ¼ 0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly. Keywords: serotonin transporter; polymorphism; cognition; memory; genes; associationIn an increasingly long-lived population severe cognitive impairment, caused by either the normal ageing process or dementia, is an escalating problem that currently has no effective treatment. Cognitive ability and its rate of decline are highly heritable and both have been shown to predict dementia onset. [1][2][3][4] Of the 13 quantitative trait loci (QTL) currently associated with the level of cognitive ability in normal individuals the most widely reported are located in genes involved in synaptic transmission. 5 These comprise the adrenergic receptor 2A, catechol-O-methyltransferase, dopamine receptor D2, cholinergic muscarinic 2 receptor, brain-derived neurotrophic factor, metabotrophic glutamate receptor 3 and the serotonin receptor 2A. [6][7][8][9][10][11][12][13] To date only the apolipoprotein E e4 allele has been associated with cognitive decline in nondemented individuals and this finding has been challenged. [14][15][16][17][18][19] Serotonin has been shown to play a role in brain development and cognitive functioning. 20,21 There is also a decrease in total brain serotonin with age that may predispose the elderly to depression, dementia and cognitive dysfunction. 22 Despite the importance of serotonin as a modulator of memory and learning the influence of two functional polymorphisms (HTTLPR and VNTR2) in the SLC6A4 gene, which codes for a protein responsible for the reuptake of serotonin, have n...

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Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

et al. 2005

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“…The 81 participants were drawn from a larger sample of 354 healthy, young Swiss subjects of Caucasian origin (de Quervain et al, 2003). The 354 volunteers were university students and employees/trainees recruited at the university of Zurich and via advertisements in local newspapers.…”

Section: Subjectsmentioning

confidence: 99%

“…and 24 h.) was assessed during two consecutive days using the Rey-15-figures free recall test , the recurring figures recognition test (Kimura, 1963), and an in-house developed verbal free recall test of 30 common German words, a test already applied and described in other publications (Papassotiropoulos et al, 2005a;de Quervain et al, 2003). The difficult inhouse verbal free recall test had been developed to avoid ceiling effects that commonly occur when investigating cognitively high functioning subjects such as university students with other verbal memory tests.…”

Section: Neuropsychologymentioning

confidence: 99%

“…gene , for the apolipoprotein E (ApoE) gene (Nauck et al, 2000), for the serotonin 2a receptor (5-HT2a; rs6314) gene (de Quervain et al, 2003), and for the prion protein (PrnP; rs1799990) gene (Papassotiropoulos et al, 2005a). We also controlled for nonrandom genetic heterogeneity (hidden population structures) by genotyping each subject for 27 unlinked SNPs located in non-genic regions distributed over all autosomes (Papassotiropoulos et al, 2005b).…”

Section: Genotypingmentioning

confidence: 99%

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A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

Hänggi

Mondadori

Buchmann

et al. 2011

Neurobiology of Aging

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There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain beta-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TT-homozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between. Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TT-homozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences beta-amyloid metabolism. CYP46 C-carriers are privileged both in terms of beta-amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated. AbstractThere is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain -amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TThomozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between.Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TThomozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences -amyloid metabolism. CYP46 C-carriers are privileged both in terms of -amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated. Keywords:Cholesterol metabolism; Single nucleotide polymorphism; CYP46 (cholesterol 24S-hydroxylase); Parahippocampal and hippocampal morphology; Alzheim...

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“…Recent studies indicate that several molecules are related to memory performance. [1][2][3][4] A whole genome association study covering more than 500,000 single nucleotide polymorphisms (SNPs) indicated that the protein called KIBRA is associated with human episodic memory performance, which depends on the function of the hippocampus, in young and middle-aged people. 5) The SNP in the ninth intron of the KIBRA gene is also associated with memory performance in elderly people and with the age-dependent risk of Alzheimer's disease.…”

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confidence: 99%

KIBRA Co-Localizes with Protein Kinase Mζ (PKMζ) in the Mouse Hippocampus

Yoshihama¹,

Hirai²,

Ohtsuka³

et al. 2009

Bioscience, Biotechnology, and Biochemistry

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KIBRA is a WW domain-containing protein that can bind to protein kinase C (PKC ). The SNP of the ninth intron of the KIBRA gene is associated with human episodic memory performance. Protein kinase M (PKM ), a brain-specific variant of PKC , plays important roles in memory formation. Here we examined the interaction of KIBRA and PKM in the adult mouse brain. Immunoprecipitation using newly-raised anti-KIBRA antibody revealed the interaction between KIBRA and PKM in the brain. KIBRA was colocalized with PKM in a single cultured neuron. Distribution analysis by immunohistochemistry and in situ hybridization indicated that KIBRA was highly localized with PKM in the hippocampal CA1, CA3, and dentate gyrus. These results suggest that KIBRA functions in memory performance via interaction with PKM .

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A functional genetic variation of the 5-HT2a receptor affects human memory

Cited by 129 publications

References 9 publications

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

KIBRA Co-Localizes with Protein Kinase Mζ (PKMζ) in the Mouse Hippocampus

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