Molecular Mechanisms of Dendritic Abnormalities Related to D-Serine Deficiency

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DESCRIPTION (provided by applicant): There is significant evidence that N-methyl-D-aspartate receptor (NMDAR) hypofunction is a core etiological component of schizophrenia. Serine racemase null mutant (SRKO) mice have hypofunctional NMDAR signaling and exhibit reductions in cortical dendritic morphology, similar to what is observed in schizophrenia. The proposed experiments will examine NMDAR-dependent molecular mechanisms responsible for producing the dendritic alterations in SRKO mice. Calcium (Ca2+) influx through NMDARs activates Ca2+/calmodulin (CaM) kinase (CaMK) and mitogen-activated protein kinase (MAPK) signaling. These pathways modulate cAMP/Ca2+ response element binding protein (CREB)-dependent transcription and are involved in NMDAR activity-dependent changes in dendritic plasticity. Aim 1 will determine whether NMDAR hypofunction negatively impacts the activity of CaMK and MAPK signaling in the prefrontal cortex (PFC). microRNAs (miRs) have been implicated in the pathophysiology of schizophrenia. They regulate neural plasticity by controlling the translation of target mRNAs. miR-132 is enriched in neurons, regulates basal and activity-induced neurite outgrowth, and its expression is regulated by CREB. The transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) is a target of miR-132 regulation and modulates activity-dependent dendritic patterning. Aim 2 will determine if NMDAR hypofunction reduces the CREB-mediated transcription of miR-132 in the PFC, and the mRNA and protein levels of MeCP2. Primary cortical cultures will be used to directly test whether miR-132 over-expression enhances dendritic morphology and reduces MeCP2 levels. Cognitive disturbances are a well-defined component of schizophrenia and are coupled with altered functioning of the PFC, the brain region most associated with dendritic abnormalities. Clinical evidence suggests that typical antipsychotics are not effective, while atypical antipsychotics are associated with some cognitive benefit. D-serine and N[3-(4'-fluorophenyl)-3-(4' phenylphenoxy) propyl] sarcosine (NFPS), drugs that enhance NMDAR signaling via the glycine modulatory site (GMS), have pro-cognitive effects in pharmacological animal models of schizophrenia. However, little is known about how antipsychotics and GMS modulators regulate dendritic morphogenesis. Therefore, Aim 3 will use cultured cortical neurons from WT and SRKO mice to compare the ability of typical and atypical antipsychotics, as well as D-serine and NFPS, to affect dendritic plasticity.