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.

Public Health Relevance

Clinically available drugs for schizophrenia are not effective at treating the cognitive deficits. The current research aims to discover new underlying causes of the disease in the hopes of developing novel acting therapeutics that will more completely treat the illness.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F01-L (20))
Program Officer
Vogel, Michael W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mclean Hospital
United States
Zip Code
Ishiwata, Sayuri; Umino, Asami; Balu, Darrick T et al. (2015) Neuronal serine racemase regulates extracellular D-serine levels in the adult mouse hippocampus. J Neural Transm (Vienna) 122:1099-103
Balu, Darrick T; Takagi, Shunsuke; Puhl, Matthew D et al. (2014) D-serine and serine racemase are localized to neurons in the adult mouse and human forebrain. Cell Mol Neurobiol 34:419-35
Balu, Darrick T; Li, Yan; Puhl, Matthew D et al. (2013) Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. Proc Natl Acad Sci U S A 110:E2400-9
Coyle, Joseph T; Basu, Alo; Benneyworth, Michael et al. (2012) Glutamatergic synaptic dysregulation in schizophrenia: therapeutic implications. Handb Exp Pharmacol :267-95
Balu, Darrick T; Basu, Alo C; Corradi, John P et al. (2012) The NMDA receptor co-agonists, D-serine and glycine, regulate neuronal dendritic architecture in the somatosensory cortex. Neurobiol Dis 45:671-82
Balu, Darrick T; Coyle, Joseph T (2012) Neuronal D-serine regulates dendritic architecture in the somatosensory cortex. Neurosci Lett 517:77-81
Balu, Darrick T; Coyle, Joseph T (2011) Glutamate receptor composition of the post-synaptic density is altered in genetic mouse models of NMDA receptor hypo- and hyperfunction. Brain Res 1392:1-7
Balu, Darrick T; Coyle, Joseph T (2011) Neuroplasticity signaling pathways linked to the pathophysiology of schizophrenia. Neurosci Biobehav Rev 35:848-70