BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

• Type of Material: Article
• Authors: Dan Zhu, Emory University; ChenChen Li, Emory University; Andrew M. Swanson, Emory University; Rosa Villalba, Emory University; Jidong Guo, Emory University; Shannon Matheny, Emory University; Tatsuro Murakami, National Institutes of Natural Sciences; Jason R. Stephenson, Emory University; Sarah Daniel, Emory University; Masaki Fukata, National Institutes of Natural Sciences; Randy Hall, Emory University; Jeffrey James Olson, Emory University; Gretchen Neigh, Emory University; Yoland Smith, Emory University; Donald Rainnie, Emory University; Erwin Van Meir, Emory University
• Language: English
• Date: 2015-04-01
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2015, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI74603
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 125
• Issue: 4
• Start Page: 1497
• End Page: 1508
• Grant/Funding Information: 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.
• Research Categories: Health Sciences, General; Biology, Neuroscience

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.