NMDA receptor hypofunction contributes to the dendritic dysplasia in schizophreni

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DESCRIPTION (provided by applicant): Schizophrenia is a complex mental disorder that affects 1% of the population worldwide. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity that is associated with reductions in dendritic spine density and atrophy of the hippocampus and cortex. The cause of these synaptic disturbances likely involves a large number of risk genes and pathways, with many of the strongest candidates interacting directly with the N-methyl-D-aspartate receptor (NMDAR). Although there is significant evidence suggesting that NMDAR hypofunction contributes to the pathophysiology of schizophrenia, there is little known about the events downstream of the NMDAR that are responsible for regulating dendritic plasticity in vivo. Moreover, it is unclear whether genetic insults that perturb glutamatergic transmission by distinct molecular mechanisms impinge on convergent signaling cascades. Thus, the goals of this proposal are to utilize two mutant mouse models with impaired glutamatergic transmission, serine racemase deficient (SR-/-) and dysbindin deficient (dys-/-) mice, to identify disturbances in common final pathways regulated by NMDAR activity that contribute to impairments in hippocampal neuroplasticity, and determine whether these deficiencies can be reversed by pharmacological intervention. Our laboratory has generated a mutant mouse that lacks SR, the enzyme that converts L-serine to D-serine, which produces a 90% reduction in D-serine coupled with NMDAR hypofunction. This lack of D-serine results in decreased global NMDAR-mediated neurotransmission and reduced sensitivity to the induction of LTP in the hippocampus. My preliminary findings have shown that the hippocampal abnormalities observed in schizophrenia are recapitulated in our SR-/- mice, in that SR-/- mice have reduced: dendritic spine density on dentate granule cells (DGCs), BDNF mRNA and protein, phospho-TrkB (active form), phospho-Akt (active form), and expression of the primary, precursor, and mature transcripts of miR-132. Aim 1 of this proposal, which will be completed during the initial 2 year mentored K99 phase, will determine the molecular mechanisms responsible for the reduced miR-132 expression in SR-/- mice, test whether miR-132 dysregulation is responsible for their dendritic abnormalities, and determine whether reversing the dendritic spine abnormalities in SR-/- mice via lenti-miR-132 overexpression restores their cognitive function. Aims 2 and 3 will be completed during the subsequent 3-year independent R00 phase. Aim 2 will determine whether chronic D-serine or TrkB agonist treatment can reverse the dendritic, neurotrophic, and miR-132 expression abnormalities in SR-/- mice. Aim 3 will determine if dys-/- mice, which also have impaired glutamatergic transmission, have dendritic spine deficits that are associated with reductions in BDNF/Akt signaling and miR-132, similar to what is observed in SR-/- mice. In sum, this proposal will help to elucidate the mechanisms associated with NMDAR hypofunction that are responsible for causing the synaptic deficits and impaired neuroplasticity in schizophrenia. These novel pathways can then be targeted for therapeutic intervention in schizophrenia, as well as other brain and psychiatric disorders that exhibit dendritic spine pathologies.