PSD-Zip70 Deficiency Causes Prefrontal Hypofunction Associated with Glutamatergic Synapse Maturation Defects by Dysregulation of Rap2 Activity.
Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of psychiatric and neurodevelopmental disorders. The prefrontal cortex (PFC) is particularly important for executive functions such as working memory, cognition, and emotional control, which are impaired in the disorders. PSD-Zip70 (Lzts1/FEZ1) is a postsynaptic density (PSD) protein predominantly expressed in the frontal cortex, olfactory bulb, striatum, and hippocampus. Here we found that PSD-Zip70 knock-out (PSD-Zip70KO) mice exhibit working memory and cognitive defects, and enhanced anxiety-like behaviors. These abnormal behaviors are caused by impaired glutamatergic synapse transmission accompanied by tiny-headed immature dendritic spines in the PFC, due to aberrant Rap2 activation, which has roles in synapse formation and plasticity. PSD-Zip70 modulates the Rap2 activity by interacting with SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) in the postsynapse. Furthermore, suppression of the aberrant Rap2 activation in the PFC rescued the behavioral defects in PSD-Zip70KO mice. Our data demonstrate a critical role for PSD-Zip70 in Rap2-dependent spine synapse development in the PFC and underscore the importance of this regulation in PFC-dependent behaviors.


CONCLUSIONS
PSD-Zip70 deficiency causes behavioral defects in working memory and cognition, and enhanced anxiety due to prefrontal hypofunction. This study revealed that PSD-Zip70 plays essential roles in glutamatergic synapse maturation via modulation of the Rap2 activity in the PFC. PSD-Zip70 interacts with both SPAR (spine-associated RapGAP) and PDZ-GEF1 (RapGEF) and modulates the Rap2 activity in postsynaptic sites. Our results provide a novel Rap2-specific regulatory mechanism in synaptic maturation involving PSD-Zip70.
Department of Neuroscience, Institute of Biomedical Sciences, School of Medicine, Iwate Medical University, 2-1-1 Yahaba, Shiwa 028-3694, Japan, and.
Taira
T
Mayanagi
Education and Research Support Center, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Japan.
Hiroki
http://orcid.org/0000-0001-5911-609X
H
Yasuda
Department of Neuroscience, Institute of Biomedical Sciences, School of Medicine, Iwate Medical University, 2-1-1 Yahaba, Shiwa 028-3694, Japan, and ksobue@iwate-med.ac.jp.
Kenji
K
Sobue
D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology*; D021641:Recognition, Psychology / Q000502:physiology; D013569:Synapses / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
C574993:Lzts1 protein, mouse; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D018698:Glutamic Acid; C492137:Rap2a protein, mouse; D020668:rap GTP-Binding Proteins
PSD-Zip70; Rap2; glutamatergic synapse; maturation; prefrontal cortex; spine