Recognition deficits in mice carrying mutations of genes encoding BLOC‐1 subunits pallidin or dysbindin

Abstract

Numerous studies have implicated DTNBP1, the gene encoding dystrobrevin-binding protein or dysbindin, as a candidate risk gene for schizophrenia, though this relationship remains somewhat controversial. Variation in dysbindin, and its location on chromosome 6p, has been associated with cognitive processes, including those relying on a complex system of glutamatergic and dopaminergic interactions. Dysbindin is one of the seven protein subunits that comprise the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin protein levels are lower in mice with null mutations in pallidin, another gene in the BLOC-1, and pallidin levels are lower in mice with null mutations in the dysbindin gene, suggesting that multiple subunit proteins must be present to form a functional oligomeric complex. Furthermore, pallidin and dysbindin have similar distribution patterns in a mouse and human brain. Here, we investigated whether the apparent correspondence of pallid and dysbindin at the level of gene expression is also found at the level of behavior. Hypothesizing a mutation leading to underexpression of either of these proteins should show similar phenotypic effects, we studied recognition memory in both strains using the novel object recognition task (NORT) and social novelty recognition task (SNRT). We found that mice with a null mutation in either gene are impaired on SNRT and NORT when compared with wild-type controls. These results support the conclusion that deficits consistent with recognition memory impairment, a cognitive function that is impaired in schizophrenia, result from either pallidin or dysbindin mutations, possibly through degradation of BLOC-1 expression and/or function.

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

“…This set of behavioral and cognitive phenotypes differentiates the spp mice from the widely used sdy mice and offers a novel model of dysbindin alterations that may be used to study specific recognition memory deficits. Our results corroborate recent findings of recognition deficits in dysbindin and pallidin deletion mouse models that further highlight a potential link between dysbindin alterations and recognition processes. Pallidin is a related biogenesis of lysosome‐related organelles complex 1 (BLOC‐1) protein that is expressed in the brain and may interact with dysbindin to produce phenotypic variation .…”

Hermansky–Pudlak syndrome: Mutation update

“…For example, the absence of platelet delta granules is currently essential for the HPS diagnosis, but a subset of subjects with BLOC‐1 may have normal/decreased platelet delta granules and may therefore not be considered for an HPS diagnosis. In addition, reported brain‐associated functions of BLOC‐1 (A. Ito et al, 2018; Newell‐Litwa et al, 2010; Spiegel, Chiu, James, Jentsch, & Karlsgodt, 2015) may underlay a neurologic phenotype of BLOC‐1 deficiency. Recognition of these features may facilitate the diagnosis of affected individuals with HPS subtypes associated with BLOC‐1 defects.…”

BLOC-1 deficiency causes alterations in amino acid profile and in phospholipid and adenosine metabolism in the postnatal mouse hippocampus

“…Following reports of a possible association between common variants in the human dysbindin-encoding gene and schizophrenia 15–18 , a number of studies have found behavioural and electrophysiological abnormalities in the sandy mice (reviewed in refs 5 and 6), with a subset of these behavioural abnormalities recently reported for pallid mice as well 19 . In addition, pallid mice showed enhanced physiological and behavioural responses to morphine administration compared to the wild-type (WT) C57BL/6J strain.…”