Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

Sanjeev K Bhardwaj,Lalit K Srivastava,Richard T Ryan,Tak Pan Wong

doi:10.3389/fnbeh.2015.00072

Abstract

The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR) family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI) function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy) mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S)-3, 5-dihydroxyphenylglycine] (DHPG)-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2). This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5) or in another mGluRI signaling pathway, i.e., protein kinase C (PKC). Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD) at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1, 3-diphenyl-1H-pyrazol-5-yl benzamide), a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

Highlights

The dystrobrevin binding protein 1 gene, coding for dysbindin-1 protein, was one of the first candidate risk genes reported for schizophrenia (Straub et al, 2002)
In order to find out if mGluRI signaling deficit in sdy mice is specific to extracellular signal regulated kinase 1/2 (ERK1/2) pathway, we measured the level of phospho-protein kinase C (PKC) in synaptoneurosomes incubated with DHPG
In order to investigate if deficits in ERK1/2 phosphorylation in sdy animals are ameliorated by mGluR5 positive allosteric modulator (PAM) CDPPB, synaptoneurosomes were incubated with Vehicle, DHPG (5 μM), CDPPB (5 μM) or CDPPB (5 μM) + DHPG (5 μM)

Summary

Introduction

The dystrobrevin binding protein 1 (dtnbp1) gene, coding for dysbindin-1 protein, was one of the first candidate risk genes reported for schizophrenia (Straub et al, 2002). The evidence from human genetic studies is strengthened by post-mortem data showing reductions in dysbindin-1 protein and mRNA in the hippocampus and prefrontal cortex (PFC) of schizophrenia brains (Weickert et al, 2008; Tang et al, 2009a). Studies from ours and other groups reveal that dysbindin deficiency in sdy mice leads to a number of cognitive and social behavioral impairments, e.g., deficits in spatial and working memory (Cox et al, 2009; Jentsch et al, 2009; Karlsgodt et al, 2011), object recognition memory (Bhardwaj et al, 2009), fear memory (Bhardwaj et al, 2009), and social interaction (Hattori et al, 2008). Reductions in presynaptic glutamate release probability and a decrease in NMDA receptor mediated currents in the PFC of sdy mice have been reported (Tang et al, 2009b; Karlsgodt et al, 2011). The behavioral significance of glutamatergic abnormalities in the dysbindin-deficient mice are, unclear

Methods

Results

Conclusion