BAI1 regulates spatial learning and synaptic plasticity in the hippocampus
Dan Zhu, … , Donald G. Rainnie, Erwin G. Van Meir
Dan Zhu, … , Donald G. Rainnie, Erwin G. Van Meir
Published March 9, 2015
Citation Information: J Clin Invest. 2015;125(4):1497-1508. https://doi.org/10.1172/JCI74603.
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Research Article Neuroscience

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

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.

Authors

Dan Zhu, Chenchen Li, Andrew M. Swanson, Rosa M. Villalba, Jidong Guo, Zhaobin Zhang, Shannon Matheny, Tatsuro Murakami, Jason R. Stephenson, Sarah Daniel, Masaki Fukata, Randy A. Hall, Jeffrey J. Olson, Gretchen N. Neigh, Yoland Smith, Donald G. Rainnie, Erwin G. Van Meir

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Figure 6

Bai1–/– mice have reduced PSD-95 protein levels.

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Bai1–/– mice have reduced PSD-95 protein levels. (A) PSD-95 protein lev...
(A) PSD-95 protein levels were reduced by approximately 50% in brains of 2-week-old pups and 6-month-old adult KO mice, while expression levels of NMDAR1, CaMKII, and presynaptic marker synaptophysin (Syn) remained unchanged. Blots shown are from samples that were run in parallel. Quantification of PSD-95 is shown on the right (n = 6; **P < 0.01 by 2-tailed Student’s t test). (B) WB showing that PSD-95 protein levels were reduced in neocortex, hippocampus, and cerebellum of adult mice, while BAIAP2 expression levels remained unchanged. (C) Substantial reduction of PSD-95 in the PSD fraction of adult KO mice. Homo, cell homogenate. (D) Quantitative RT-PCR showed that PSD-95 mRNA levels were not reduced in KO mice. (E) PSD-95 was more rapidly degraded in cultured primary cortical neurons from KO mice. CHX (30 μg/ml) was added to block de novo protein translation in high-density dissociated cortical neurons for 0, 8, and 24 hours. Cell lysates were collected and subjected to WB analysis. Relative band intensities are indicated. All histograms show the mean ± SEM. All blots show representative images from 3 independent experiments with similar results.