Single point mutation on the gene encoding dysbindin results in recognition deficits

Abstract

The dystrobrevin-binding protein 1 (DTNBP1) gene is a candidate risk factor for schizophrenia and has been associated with cognitive ability in both patient populations and healthy controls. DTNBP1 encodes dysbindin protein, which is localized to synaptic sites and is reduced in the prefrontal cortex and hippocampus of patients with schizophrenia, indicating a potential role in schizophrenia etiology. Most studies of dysbindin function have focused on the sandy (sdy) mice that lack dysbindin protein and have a wide range of abnormalities. In this study, we examined dysbindin salt and pepper (spp) mice that possess a single point mutation on the Dtnbp1 gene predicted to reduce, but not eliminate, dysbindin expression. By western blot analysis, we found that spp homozygous (spp -/-) mutants had reduced dysbindin and synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex, but unaltered levels in hippocampus. Behaviorally, spp mutants performed comparably to controls on a wide range of tasks assessing locomotion, anxiety, spatial recognition and working memory. However, spp -/- mice had selective deficits in tasks measuring novel object recognition and social novelty recognition. Our results indicate that reduced dysbindin and SNAP-25 protein in the prefrontal cortex of spp -/- is associated with selective impairments in recognition processing. These spp mice may prove useful as a novel mouse model to study cognitive deficits linked to dysbindin alterations. Our findings also suggest that aspects of recognition memory may be specifically influenced by DTNBP1 single nucleotide polymorphisms or risk haplotypes in humans and this connection should be further investigated.

Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

“…Most recently, behavioral and cognitive phenotypes have been investigated in mice containing a single point mutation in the salt and pepper (spp) allele of DTNBP1 (Chang et al, 2018). While spp mutants did not exhibit any deficits in working memory (Tmaze alternation task), some deficits in aspects of recognition memory performance were observed.…”

Sleep/Wake Disruption in a Mouse Model of BLOC-1 Deficiency

“…BLOC-1 expression in the mouse central nervous system is developmentally regulated with higher expression during perinatal periods ( Ghiani et al, 2010 ), and in its absence, hippocampal neurones in cultures exhibit defective neurite outgrowth ( Ghiani et al, 2010 ; Ito et al, 2010 ; Ma et al, 2011 ). Behavioural and neurophysiological abnormalities have been reported in the sandy mouse, a naturally occuring mutant carrying an in-frame deletion in the gene encoding dysbindin (reviewed by Ghiani and Dell’Angelica, 2011 , for examples see Bhardwaj et al, 2009 ; Cox et al, 2009 ; Ryder and Faundez, 2009 ; Talbot, 2009 ; Papaleo et al, 2012 ; Carr et al, 2013 ; Glen et al, 2014 ; Larimore et al, 2014 , 2017 ; Bhardwaj et al, 2015a ; Yuan et al, 2016 ) as well as in other dysbindin-mutants ( Petit et al, 2017 ; Chang et al, 2018 ). Importantly, Spiegel et al (2015) reported that the pallid and sandy lines show similar impairment of social recognition memory.…”

Behavioral Tasks Evaluating Schizophrenia-like Symptoms in Animal Models: A Recent Update

“…Recent studies employing this behavior analysis have revealed cognitive impairment in various developmental, pharmacological, and genetic rodent models of schizophrenia (Table 3 ) including mice subjected to MIA by LPS on embryonic day 8 (E8) [ 208 ], conditional deletion of the intraflagellar transport 88 gene in mice [ 199 ], mice with null mutation in the pallidin or dysbindin gene, both of which comprise the biogenesis of lysosome-related organelles complex 1 [ 209 ]; dysbindin salt and pepper mice, which possess a single point mutation on the Dtnbp1 gene [ 210 ]; mice treated with the muscarinic acetylcholine system antagonist, scopolamine (2 mg/kg, intraperitoneal), l-methionine treated mice [ 211 ]; PCP + Δ9-THC treated mice [ 62 ], mice treated subchronically with PCP [ 113 , 125 ], and alpha7-nicotinic acetylcholine receptor (α7-nAChR) KO mice [ 186 ]. Recent studies using animal models of schizophrenia have found that various factors could lead to decreased visual learning and memory.…”