Impaired long-term memory retention and working memory in sdy mutant mice with a deletion in Dtnbp1, a susceptibility gene for schizophrenia

Abstract

Background: Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. The dystrobrevin-binding protein 1 (DTNBP1: dysbindin-1) gene is a major susceptibility gene for schizophrenia. Genetic variations in DTNBP1 are associated with cognitive functions, general cognitive ability and memory function, and clinical features of patients with schizophrenia including negative symptoms and cognitive decline. Since reduced expression of dysbindin-1 has been observed in postmortem brains of patients with schizophrenia, the sandy (sdy) mouse, which has a deletion in the Dtnbp1 gene and expresses no dysbindin-1 protein, could be an animal model of schizophrenia. To address this issue, we have carried out a comprehensive behavioral analysis of the sdy mouse in this study.

Dysbindin-1 and NRG-1 gene expression in immortalized lymphocytes from patients with schizophrenia

“…[2][3][4] Furthermore, the Sandy mouse, which expresses no dysbindin-1, has been reported to have behavioral abnormalities, cognitive deficits and a synaptic dysfunction that is related to the pathophysiology of schizophrenia. [5][6][7] Identified risk variants of NRG-1 are associated with the reduced white matter volume that is observed in schizophrenic brains. 8 The NRG-1 gene spans 1.2 Mb 9 and gives rise to many structurally and functionally distinct isoforms, through alternative promoter usage.…”

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

“…305 Recently, there has been a proliferation of animal model studies that have examined Dtnbp1 in the sandy mouse, which does not express the Dtnbp1 gene. 306 Studies have shown that Dtnbp1 knockout mice display reduced social inter action, impairments in long-term memory retention, spatial memory and working memory, as well as hyperactivity. [306][307][308][309] These mice also have a reduction in the steady state levels of synapsin in the hippocampal formation, a reduction in DA, but normal glutamate levels.…”

“…306 Studies have shown that Dtnbp1 knockout mice display reduced social inter action, impairments in long-term memory retention, spatial memory and working memory, as well as hyperactivity. [306][307][308][309] These mice also have a reduction in the steady state levels of synapsin in the hippocampal formation, a reduction in DA, but normal glutamate levels. 308,309 Given the findings from both animal model and human association studies, it would appear that DTNBP1 is an influential gene in the development of schizophrenia-related biomarkers and schizophrenia, respectively.…”

Cellular and Circuit Models of Increased Resting State Network Gamma Activity in Schizophrenia

“…Some studies indicate that these mice have increased T-maze performance while other find the converse Takao et al, 2008;Karlsgodt et al, 2011;Papaleo et al, 2012). Alternatively, dysbindin knockout mice display impaired spatial reference memory and novel object recognition performance (Karlsgodt et al, 2011;Papaleo et al, 2012).…”