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 4

Bai1–/– hippocampal CA1 neurons have normal dendritic arborization and spine morphology.

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Bai1–/– hippocampal CA1 neurons have normal dendritic arborization and ...
(A) Representative images of biocytin-filled CA1 neurons from adult WT and KO mice show normal dendritic arborization in KO mice. Scale bar: 50 μm. (B) Representative images from apical segments of WT and KO neurons show unaffected dendritic spine density and morphology. Scale bars: 2 μm. (C) No significant difference in dendritic spine density was observed between WT and KO CA1 neurons. Secondary dendritic segments were captured from basal dendrites, proximal apical dendrites (50–100 μm from the soma), middle apical dendrites (100–150 μm from the soma), and distal apical dendrites (>150 μm from the soma). n = 5 mice/group; P = 0.55. (D) Dendritic spine morphology was not affected in KO neurons. Spines were classified as stubby, mushroom, or thin and were quantified. n = 5 mice/group; P = 0.99. All data represent the mean ± SEM and were analyzed by 2-way ANOVA.