BAI1 regulates spatial learning and synaptic plasticity in the hippocampus.
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.
Dan
D
Zhu
Chenchen
C
Li
Andrew M
AM
Swanson
Rosa M
RM
Villalba
Jidong
J
Guo
Zhaobin
Z
Zhang
Shannon
S
Matheny
Tatsuro
T
Murakami
Jason R
JR
Stephenson
Sarah
S
Daniel
Masaki
M
Fukata
Randy A
RA
Hall
Jeffrey J
JJ
Olson
Gretchen N
GN
Neigh
Yoland
Y
Smith
Donald G
DG
Rainnie
Erwin G
EG
Van Meir
D042501:Angiogenic Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000098:blood supply; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D059032:Learning Curve; D007859:Learning Disabilities / Q000235:genetics* / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008569:Memory Disorders / Q000235:genetics* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000648:ultrastructure; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D065853:Spatial Learning / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D054875:Ubiquitination
C524949:Adgrb1 protein, mouse; D042501:Angiogenic Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D051528:Guanylate Kinases