Reduced Dysbindin Expression Mediates N-Methyl-D-Aspartate Receptor Hypofunction and Impaired Working Memory Performance

Abstract

Schizophrenia is a substantially heritable disorder associated with disrupted neural transmission, as well as dysfunction of brain systems involved in higher cognitive processes. Among the several putative candidate genes for schizophrenia, the gene encoding dystrobrevin-binding-protein-1 (aka dysbindin) is associated with cognitive impairments, including memory and attention deficits, in both schizophrenia patients and non-schizophrenic individuals. The mechanism underlying these deficits is thought to be based in changes in glutamatergic and dopaminergic function within corticostriatal networks, circuitry known to be critical for schizophrenia. Recent support for this hypothesis derives from the study of mice with a null mutation in the dysbindin gene that exhibit memory dysfunction and abnormalities in excitatory neurotransmission in prefrontal and hippocampal networks. At a cellular level, dysbindin is thought to mediate pre-synaptic glutamatergic transmission. Here, we investigated whether loss of dysbindin expression also affects postsynaptic NMDA receptor function. We show that decreases in dysbindin are associated with specific decreases in NMDA-evoked currents in prefrontal pyramidal neurons, as well as decreases in expression of the obligatory NMDA receptor subunit (NR1). Furthermore, the degree of NR1 expression directly correlates with performance on a spatial working memory task, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression. These data show a significant down-regulation of NMDA receptors due to dysbindin deficiency and illuminate molecular mechanisms mediating the association between dysbindin insufficiency and cognitive impairments associated with schizophrenia, encouraging study of the dysbindin/NR1 expression association in humans with and at risk for the disease.

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

“…We argue that heterozygous LRFN2 deletion likely contributes to the learning disability seen in the family members because: (i) LRFN2 co-localizes with NR1 in the postsynaptic region; and (ii) dysfunction of NMDARs have been shown to alter excitatory synapse functioning and WM processes. [27][28][29] To date, two cases with deletions encompassing LRFN2 are available in public databases (ClinGen or Decipher (295383)). Their deletions were larger than that reported here (respectively, 7.87 and 3.19 Mb) and included numerous genes in the vicinity of LRFN2.…”

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

“…Thus, the role of reduced glutamatergic transmission through NMDA hypofunction is a converging hypothesis in the development of schizophrenia that may be modeled by the present work. Alternatively, dysbindin-1 is also found in PVpositive neurons, and recent work has indicated a direct role for dysbindin in NMDA receptor trafficking (16,34,72). Therefore, dysbindin-1 may impact NMDA activity in interneurons both preand postsynaptically.…”

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).…”

“…Alternatively, dysbindin knockout mice display impaired spatial reference memory and novel object recognition performance (Karlsgodt et al, 2011;Papaleo et al, 2012). Freely moving rats treated prenatally with MAM have a diminished gamma band response during task performance and display working memory deficits (Flagstad et al, 2005;Moore et al, 2006).…”

“…Specifically, agents that make rodent increase their locomotor activity tend to have psychotomimetic properties in humans (Swerdlow et al, 2000;Jones et al, 2011). Among genetic models with increased baseline gamma activity, increased locomotor activity has been noted in NR1 hypomorphs (Gandal et al, 2012c), pyramidal cell selective NR1 knockout mice (Tatard-Leitman et al, 2015), mice with developmental knock out of NR1 in a subset of interneurons Erbb4 conditional knockout mice (del Pino et al, 2013) and dysbindin knockout mice (Karlsgodt et al, 2011;Papaleo et al, 2012). Similarly, developmental lesion models including both MAM-treated and NVHL rats exhibit hyperactivity (Lipska et al, 1993;Lipska and Weinberger, 2000).…”