Research

Identification of GRIN3 as a component of the NMDA receptor complex. Through previous work at Harvard Medical School, we identified GRIN3 as a novel subunit of NMDA-type glutamate receptors. At the time of this finding, GRIN1 and GRIN2 had been identified as NMDA receptor subuits. We showed that GRIN3 forms biochemical complex with GRIN1 and GRIN2. We then genetically knocked out GRIN3 gene in mice to show that GRIN3 modifies NMDA-evoked currents and regulates dendritic spine morphology in vivo.

Identification of GRIN3 as a neuroprotective protein in a mouse model of stroke.  While working previously at Sanford Burnham Prebys Medical Discovery Institute, we led the study in which we constructed transgenic mice overexpressing GRIN3 in the brain, not clearly understood at the time, and studied its effects. We have shown that GRIN3 overexpression leads to the reduction in the size of stroke and thus identified GRIN3 as a neuroprotective protein.

Identification of takusan proteins in the mouse brain.  Briefly, we originally identified takusan as a differentially expressed gene in GRIN3 knock out mice.  We then discovered that the mouse genome carries ~200 homoologous genes encoding variants of takusan.  Overexpression of takusan proteins in cultured neurons leads to the modification of dendritic spines.  Importantly, we showed that engineered takusan proteins can protect synapses from Aβ induced damages.

The identification of the transcription factor MEF2 (myocyte enhancer factor-2) as a critical molecule in neuronal development. In addition, we have discovered a novel etiology of Intellectual and Developmental Disabilities (IDD) and Autism-Spectrum Disorders (ASD) based on genetic alterations in one of MEF2 subtypes, MEF2C. In collaboration with the Lipton Lab, we recently generated a conditional brain knockout of Mef2c in mice, which resulted in a decrease in neurogenesis, fewer synapses, and an IDD- and ASD-related phenotype in behavioral tests (published in PNAS). Subsequently, six other laboratories reported that microdeletion of one copy of chromosome regions containing MEF2C in humans resulted in IDD, ASD, and other neurological disorders, making our findings in mice clinically relevant.

Nakanishi Lab Grants

NIH/DHHS P01 “Genetic Approach to Excitatory Transmission”

California Institute of Regenerative Medicine (CIRM) “Programming Human ESC-derived Neural Stem Cells with MEF2C for Transplantation in Stroke”

Nobuki Nakanishi, PhD