About this item:

462 Views | 659 Downloads

Author Notes:

Email Address: Erwin G. Van Meir: evanmei@emory.edu

We thank Helen Zhang of Emory University’s Transgenic Mouse and Gene Targeting Core for help with generation of the Bai1–/– mouse line.

We thank Jason Schroeder and David Weinshenker of Emory University’s Rodent Behavioral Core facility for help with the mouse behavior tests Xinping Huang of the Emory University Viral Vector Core for packaging the AAV.

We thank Christine Blattner (Karlsruher Institut für Technologie, Karlsruhe, Germany) for the Myc-tagged MDM2 constructs.

We thank Emily E. Hardy for help with the marble-burying test.

The spine analysis was performed using software provided by the NINDS/CND.

The authors have declared that no conflict of interest exists.

Subjects:

Research Funding:

This work was supported by grants from the NIH (CA86335, to E.G. Van Meir and CA138292, to the Winship Cancer Institute); the Southeastern Brain Tumor Foundation (to E.G. Van Meir); the CURE Childhood Cancer Foundation (to E.G. Van Meir); the St. Baldrick’s Foundation (to E.G. Van Meir); the National Institute on Drug Abuse (NIDA) (T32 DA015040 and DA036316, to A.M. Swanson); and the National Institute of Neurological Disorders and Stroke (NINDS) and the Center for Neurodegenerative Disease (CND) (P30NS055077), in support of the Viral Vector and Microscopy Core facilities of Emory University.

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

Show all authors Show less authors

Tools:

Journal Title:

Journal of Clinical Investigation

Volume:

Volume 125, Number 4

Publisher:

, Pages 1497-1508

Type of Work:

Article | Final Publisher PDF

Abstract:

Synaptic plasticity is the ability of synapses to modulate the strength of neuronal connections; however, the molecular factors that regulate this feature are incompletely understood. Here, we demonstrated that mice lacking brain-specific angiogenesis inhibitor 1 (BAI1) have severe deficits in hippocampus-dependent spatial learning and memory that are accompanied by enhanced long-term potentiation (LTP), impaired long-term depression (LTD), and a thinning of the postsynaptic density (PSD) at hippocampal synapses. We showed that compared with WT animals, mice lacking Bai1 exhibit reduced protein levels of the canonical PSD component PSD-95 in the brain, which stems from protein destabilization. We determined that BAI1 prevents PSD-95 polyubiquitination and degradation through an interaction with murine double minute 2 (MDM2), the E3 ubiquitin ligase that regulates PSD-95 stability. Restoration of PSD-95 expression in hippocampal neurons in BAI1-deficient mice by viral gene therapy was sufficient to compensate for Bai1 loss and rescued deficits in synaptic plasticity. Together, our results reveal that interaction of BAI1 with MDM2 in the brain modulates PSD-95 levels and thereby regulates synaptic plasticity. Moreover, these results suggest that targeting this pathway has therapeutic potential for a variety of neurological disorders.

Copyright information:

© 2015, American Society for Clinical Investigation

Export to EndNote