CXCR5 Regulates Neuronal Polarity Development and Migration in the Embryonic Stage via F‑Actin Homeostasis and Results in Epilepsy‑Related Behavior

Epilepsy is a common,chronic neurological disorder that has been associated with impaired neurodevelopment and immunity.The chemokine receptor CXCR5 is involved in seizures via an unknown mechanism.Here,we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy.Subsequently,we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol-and kainic acid-induced seizures,whereas CXCR5 overexpression had the opposite effect.CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons.Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model,we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment.Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability,resulting in an increased number of seizures.Finally,our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism,namely,the disruption of neuronal polarity.

P-Rex1 Overexpression Results in Aberrant Neuronal Polarity and Psychosis-Related Behaviors

Neuronal polarity is involved in multiple developmental stages, including cortical neuron migration,multipolar-to-bipolar transition, axon initiation, apical/basal dendrite differentiation, and spine formation. All of these processes are associated with the cytoskeleton and are regulated by precise timing and by controlling gene expression. The P-Rex1(phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1) gene for example, is known to be important for cytoskeletal reorganization, cell motility, and migration. Deficiency of P-Rex1 protein leads to abnormal neuronal migration and synaptic plasticity, as well as autism-related behaviors.Nonetheless, the effects of P-Rex1 overexpression on neuronal development and higher brain functions remain unclear. In the present study, we explored the effect of P-Rex1 overexpression on cerebral development and psychosis-related behaviors in mice. In utero electroporation at embryonic day 14.5 was used to assess the influence of P-Rex1 overexpression on cell polarity and migration.Primary neuron culture was used to explore the effects of P-Rex1 overexpression on neuritogenesis and spine morphology. In addition, P-Rex1 overexpression in the medial prefrontal cortex(m PFC) of mice was used to assess psychosis-related behaviors. We found that P-Rex1 overexpression led to aberrant polarity and inhibited the multipolar-to-bipolar transition, leading to abnormal neuronal migration. In addition, P-Rex1 overexpression affected the early development of neurons, manifested as abnormal neurite initiation with cytoskeleton change,reduced the axon length and dendritic complexity, and caused excessive lamellipodia in primary neuronal culture.Moreover, P-Rex1 overexpression decreased the density of spines with increased height, width, and head area in vitro and in vivo. Behavioral tests showed that P-Rex1 overexpression in the mouse m PFC caused anxiety-like behaviors and a sensorimotor gating deficit. The appropriate P-Rex1 level plays a critical role in the developing cerebral cortex and excessive P-Rex1 might be related to psychosis-related behaviors.

KIF17 Modulates Epileptic Seizures and Membrane Expression of the NMDA Receptor Subunit NR2B

Epilepsy is a common and severe brain disease affecting>65 million people worldwide.Recent studies have shown that kinesin superfamily motor protein 17(KIF17)is expressed in neurons and is involved in regulating the dendrite-targeted transport of N-methyl-D-aspartate receptor subtype 2B(NR2B).However,the effect of KIF17 on epileptic seizures remains to be explored.We found that KIF17 was mainly expressed in neurons and that its expression was increased in epileptic brain tissue.In the kainic acid(KA)-induced epilepsy mouse model,KIF17 overexpression increased the severity of epileptic activity,whereas KIF17 knockdown had the opposite effect.In electrophysiological tests,KIF17 regulated excitatory synaptic transmission,potentially due to KIF17-mediated NR2B membrane expression.In addition,this report provides the first demonstration that KIF17 is modified by SUMOylation(SUMO,small ubiquitin-like modifier),which plays a vital role in the stabilization and maintenance of KIF17 in epilepsy.

STON2风险变异通过影响Syt1转运和突触功能导致精神分裂症样行为

Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.