TY - JOUR
T1 - Loss of the polarity protein Par3 promotes dendritic spine neoteny and enhances learning and memory
AU - Voglewede, Mikayla M.
AU - Ozsen, Elif Naz
AU - Ivak, Noah
AU - Bernabucci, Matteo
AU - Tang, Ruizhe
AU - Sun, Miao
AU - Pang, Zhiping P.
AU - Zhang, Huaye
N1 - Publisher Copyright: © 2024 The Authors
PY - 2024/7/19
Y1 - 2024/7/19
N2 - The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants of PARD3, encoding PAR3, are associated with intelligence and neurodevelopmental disorders. However, the role of Par3 in glutamatergic synapse formation and cognitive functions in vivo remains unknown. Here, we show that forebrain-specific Par3 conditional knockout leads to increased long, thin dendritic spines in vivo. In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents. Surprisingly, loss of Par3 enhances hippocampal-dependent spatial learning and memory and repetitive behavior. Phosphoproteomic analysis revealed proteins regulating cytoskeletal dynamics are significantly dysregulated downstream of Par3. Mechanistically, we found Par3 deletion causes increased Rac1 activation and dysregulated microtubule dynamics through CAMSAP2. Together, our data reveal an unexpected role for Par3 as a molecular gatekeeper in regulating the pool of immature dendritic spines, a rate-limiting step of learning and memory, through modulating Rac1 activation and microtubule dynamics in vivo.
AB - The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants of PARD3, encoding PAR3, are associated with intelligence and neurodevelopmental disorders. However, the role of Par3 in glutamatergic synapse formation and cognitive functions in vivo remains unknown. Here, we show that forebrain-specific Par3 conditional knockout leads to increased long, thin dendritic spines in vivo. In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents. Surprisingly, loss of Par3 enhances hippocampal-dependent spatial learning and memory and repetitive behavior. Phosphoproteomic analysis revealed proteins regulating cytoskeletal dynamics are significantly dysregulated downstream of Par3. Mechanistically, we found Par3 deletion causes increased Rac1 activation and dysregulated microtubule dynamics through CAMSAP2. Together, our data reveal an unexpected role for Par3 as a molecular gatekeeper in regulating the pool of immature dendritic spines, a rate-limiting step of learning and memory, through modulating Rac1 activation and microtubule dynamics in vivo.
KW - Cellular neuroscience
KW - Molecular neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85197082136&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85197082136&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.110308
DO - 10.1016/j.isci.2024.110308
M3 - Article
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 7
M1 - 110308
ER -