The impact of dystrobrevin‐binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval

Episodic memory impairment is a frequently reported symptom in schizophrenia. It has been shown to be associated with reduced neural activity of the hippocampus and prefrontal cortex. Given the high heritability of schizophrenia the question arises if alterations in brain activity are modulated by susceptibility genes and might be detectable in healthy risk allele carriers. The present study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 (P1578) of the dystrobrevin‐binding protein 1 (DTNBP1) on brain activity in 84 healthy subjects assessed by functional magnetic resonance imaging (fMRI) while they performed an episodic memory task comprising encoding and retrieval of faces. During encoding, the group of risk allele carriers (n = 29) showed enhanced neural activity in the left middle frontal gyrus (BA 11) and bilaterally in the cuneus (BA 17, 7) when compared with the nonrisk carrier group (n = 55). During retrieval, the risk group (compared to the non risk group) showed increased right hemispheric neural activity comprising the medial frontal gyrus (BA 9), inferior frontal gyrus (BA 9), and inferior parietal lobule (BA 40). Since there were no behavioral performance differences, increased neural activity of the risk group might be interpreted as a correlate of higher effort or differing cognitive strategies in order to compensate for a genetically determined slight cognitive deficit. Interestingly, the laterality of increased prefrontal activity is in accordance with the well known hemispheric encoding/retrieval asymmetry (HERA) model of episodic memory. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.

[1]  Dysbindin-1 and schizophrenia: from genetics to neuropathology. , 2004, The Journal of clinical investigation.

[2]  Robert C. Elston,et al.  Testing for Hardy-Weinberg equilibrium in small samples , 1977 .

[3]  René S. Kahn,et al.  Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis , 2004, Schizophrenia Research.

[4]  Enrico Simonotto,et al.  Event-related fMRI of word classification and successful word recognition in subjects at genetically enhanced risk of schizophrenia , 2006, Psychological Medicine.

[5]  Kristen M. Haut,et al.  The Influence of Encoding Strategy on Episodic Memory and Cortical Activity in Schizophrenia , 2005, Biological Psychiatry.

[6]  Birgit Funke,et al.  DTNBP1 genotype influences cognitive decline in schizophrenia , 2007, Schizophrenia Research.

[7]  R. Kahn,et al.  Memory impairment in schizophrenia: a meta-analysis. , 1999, The American journal of psychiatry.

[8]  Russell A. Poldrack,et al.  Elaborative Verbal Encoding and Altered Anterior Parahippocampal Activation in Adolescents and Young Adults at Genetic Risk for Schizophrenia Using fMRI , 2006, Biological Psychiatry.

[9]  Edson Amaro,et al.  Bilateral activation of the prefrontal cortex after strategic semantic cognitive training , 2006, Human brain mapping.

[10]  John G. Csernansky,et al.  Episodic memory in schizophrenia: The influence of strategy use on behavior and brain activation , 2008, Psychiatry Research: Neuroimaging.

[11]  Birgit Funke,et al.  Genetic variation in DTNBP1 influences general cognitive ability. , 2006, Human molecular genetics.

[12]  I. Tendolkar,et al.  Integrated brain activity in medial temporal and prefrontal areas predicts subsequent memory performance: human declarative memory formation at the system level , 2001, Brain Research Bulletin.

[13]  Paul J. Harrison,et al.  Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence , 2005, Molecular Psychiatry.

[14]  J. Waddington,et al.  Susceptibility genes for schizophrenia: Characterisation of mutant mouse models at the level of phenotypic behaviour , 2007, Neuroscience & Biobehavioral Reviews.

[15]  D. Barch,et al.  Imaging genetic liability to schizophrenia: systematic review of FMRI studies of patients' nonpsychotic relatives. , 2009, Schizophrenia bulletin.

[16]  Frank Baas,et al.  Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings , 2007, Behavioral and Brain Functions.

[17]  Michael J Owen,et al.  Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? , 2005, Schizophrenia bulletin.

[18]  C. Freitag,et al.  DTNBP1 (Dysbindin) Gene Variants Modulate Prefrontal Brain Function in Healthy Individuals , 2006, Neuropsychopharmacology.

[19]  E Tulving,et al.  Neuroanatomical correlates of retrieval in episodic memory: auditory sentence recognition. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Craik,et al.  Hemispheric encoding/retrieval asymmetry in episodic memory: positron emission tomography findings. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Takahisa Taguchi,et al.  Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia. , 2004, Human molecular genetics.

[22]  M C O'Donovan,et al.  The molecular genetics of schizophrenia: new findings promise new insights , 2004, Molecular Psychiatry.

[23]  M. Gill,et al.  Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study , 2007, Neuropsychologia.

[24]  M. Moscovitch,et al.  Distinct neural correlates of visual long-term memory for spatial location and object identity: a positron emission tomography study in humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Tilo Kircher,et al.  Neuregulin 1 ICE-single nucleotide polymorphism in first episode schizophrenia correlates with cerebral activation in fronto-temporal areas , 2009, European Archives of Psychiatry and Clinical Neuroscience.

[26]  R. Straub,et al.  Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. , 2002, American journal of human genetics.

[27]  F. Craik,et al.  Functional Neuroanatomy of Recall and Recognition: A PET Study of Episodic Memory , 1997, Journal of Cognitive Neuroscience.

[28]  A. Heinz,et al.  Genes and Neuroimaging: Advances in Psychiatric Research , 2008, Neurodegenerative Diseases.

[29]  J. Hart,et al.  Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. , 2003, Brain research. Cognitive brain research.

[30]  M. Lepage,et al.  Episodic memory-related activation in schizophrenia: meta-analysis , 2005, British Journal of Psychiatry.

[31]  Timothy C. Bates,et al.  Variation in the dysbindin gene and normal cognitive function in three independent population samples , 2009, Genes, brain, and behavior.

[32]  M Erb,et al.  Differential activation in parahippocampal and prefrontal cortex during word and face encoding tasks , 2001, Neuroreport.

[33]  Nadim Joni Shah,et al.  Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals , 2008, NeuroImage.

[34]  Cameron S Carter,et al.  Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. , 2005, Schizophrenia bulletin.

[35]  Charan Ranganath,et al.  Prefrontal Cortex and Long-Term Memory Encoding: An Integrative Review of Findings from Neuropsychology and Neuroimaging , 2007, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[36]  Daniel R Weinberger,et al.  Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain. , 2004, Archives of general psychiatry.

[37]  S. Heckers,et al.  Neuroimaging of declarative memory in schizophrenia. , 2001, Scandinavian journal of psychology.

[38]  R. C. Oldfield The assessment and analysis of handedness: the Edinburgh inventory. , 1971, Neuropsychologia.

[39]  M. Egan,et al.  Prefrontal neurons and the genetics of schizophrenia , 2001, Biological Psychiatry.

[40]  R. Cabeza,et al.  Imaging Cognition II: An Empirical Review of 275 PET and fMRI Studies , 2000, Journal of Cognitive Neuroscience.

[41]  D. Barch,et al.  Levels-of-Processing Effects in First-Degree Relatives of Individuals with Schizophrenia , 2007, Biological Psychiatry.

[42]  Birgit Funke,et al.  Association of the DTNBP1 locus with schizophrenia in a U.S. population. , 2004, American journal of human genetics.

[43]  Costas N. Stefanis,et al.  Impact of Schizophrenia Candidate Genes on Schizotypy and Cognitive Endophenotypes at the Population Level , 2007, Biological Psychiatry.