BAI1 regulates spatial learning and synaptic plasticity in the hippocampus
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
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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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 7

BAI1 binds MDM2 and prevents PSD-95 polyubiquitination.

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BAI1 binds MDM2 and prevents PSD-95 polyubiquitination. (A) BAI1 attenua...
(A) BAI1 attenuated PSD-95 polyubiquitination. HEK 293FT cells were transiently transfected with the indicated expression vectors. Left panel: Immunoblot (IB) detected PSD-95 and high-molecular-weight polyubiquitinated PSD-95 (arrow). Right panel: Co-IP with anti–PSD-95 antibody, followed by IB detection of ubiquitin chains (anti-HA antibody). (B) Deletion of the BAI1 QTEV motif blocked the BAI1–PSD-95 interaction (left panel), but retained the ability to inhibit PSD-95 polyubiquitination (right panel). HEK 293FT cells were transiently cotransfected with expression vectors for PSD-95 with either BAI1 WT or mutant plasmid. Antibodies used for Co-IP and IB are indicated. Blots shown are from samples that were run in parallel. (C) Co-IP shows the BAI1-MDM2 association in adult WT mouse brain. (D) Interaction of BAI1 and MDM2 in transfected HEK 293FT cells. Left: Schematic drawing of the full-length (FL) and truncated MDM2 constructs. Right: HEK 293FT cells were cotransfected with expression vectors for BAI1 and Myc-tagged full-length MDM2 or the indicated deletion mutants. (E) Overexpression of a dominant-negative MDM2 (HA-MDM2) blocked the BAI1-MDM2 (WT) interaction (left panel) and enhanced PSD-95 polyubiquitination (right panel). HEK 293FT cells were transiently transfected with the indicated expression vectors. Myc-MDM2, full-length Myc-tagged MDM2; HA-MDM2, HA-tagged N terminus of MDM2 (aa 1–215). (F) Co-IP experiments on brain extracts from 2-week- and 6-month-old WT and KO mice showed increased polyubiquitination of PSD-95 and PSD-95–MDM2 interaction in KO mouse brains. All blots show representative images from 3 independent experiments with similar results.