The schizophrenia susceptibility gene DTNBP1 modulates AMPAR synaptic transmission and plasticity in the hippocampus of juvenile DBA/2J mice

Abstract

The dystrobrevin binding protein (DTNBP) 1 gene has emerged over the last decade as a potential susceptibility locus for schizophrenia. While no causative mutations have been found, reduced expression of the encoded protein, dysbindin, was reported in patients. Dysbindin likely plays a role in the neuronal trafficking of proteins including receptors. One important pathway suspected to be affected in schizophrenia is the fast excitatory glutamatergic transmission mediated by AMPA receptors. Here, we investigated excitatory synaptic transmission and plasticity in hippocampal neurons from dysbindin-deficient sandy mice bred on the DBA/2J strain. In cultured neurons an enhancement of AMPAR responses was observed. The enhancement of AMPAR-mediated transmission was confirmed in hippocampal CA3-CA1 synapses, and was not associated with changes in the expression of GluA1–4 subunits nor an increase in GluR2-lacking receptor complexes. Lastly, an enhancement in LTP was also found in these mice. These data provide compelling evidence that dysbindin, a widely suspected susceptibility protein in schizophrenia, is important for AMPAR-mediated synaptic transmission and plasticity in the developing hippocampus.

Dysbindin-1C Is Required for the Survival of Hilar Mossy Cells and the Maturation of Adult Newborn Neurons in Dentate Gyrus

“…was found in sdy hippocampal neurons (30,31). Moreover, altered hippocampal activity was revealed by magnetic resonance imaging of the sdy mice (52).…”

Characterization of Human Hippocampal Neural Stem/Progenitor Cells and Their Application to Physiologically Relevant Assays for Multiple Ionotropic Glutamate Receptors

“…15,16 The hippocampus plays important roles in the consolidation of information from short-term memory to long-term memory and in spatial learning; it is also a brain region central to neurological disorders such as AD, schizophrenia, and epilepsy. Kravitz et al 10 showed that the density of NMDARs was decreased in the postmortem human hippocampus in patients with AD; loss of NMDARs was 11 reported that AMPAR-mediated neurotransmission was increased in hippocampal CA3−CA1 synapses of an animal model of schizophrenia, the sandy mouse, contributing to inappropriate encoding of memory. Hippocampal sclerosis is commonly observed in patients with temporal lobe epilepsy (TLE).…”

“…The hippocampus is an important brain region involved in neurological disorders such as AD, schizophrenia, and epilepsy. [10][11][12][13] Therefore, we need to develop an assay system that uses human hippocampal neurons so that we can obtain a detailed understanding of the molecular mechanisms underlying these diseases and discover novel drugs for treating them.…”

The mechanistic link between Arc/Arg3.1 expression and AMPA receptor endocytosis

“…Many neurological and neurodegenerative diseases including autism [60], Rett syndrome [61], schizophrenia [62] depression [63], epilepsy [64][65][66] and Alzheimer's disease [67] are associated with deficits in synaptic transmission and in particular, abnormalities in the trafficking of synaptic AMPAR. Defects in Arc function may underlie some of the observed changes in synaptic AMPAR trafficking and expression.…”