PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton, modulating emotional behavior.

Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders.

Synaptic plasticity in schizophrenia pathophysiology.

Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.

Association of variants in the KIF1A gene with amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30. METHODS: Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS. RESULTS: We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor. CONCLUSIONS: Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS.

PINK1-mediated Drp1S616 phosphorylation modulates synaptic development and plasticity via promoting mitochondrial fission.

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.

Synaptic plasticity in schizophrenia pathophysiology.

Schizophrenia is a severe neuropsychiatric syndrome with psychotic behavioral abnormalities and marked cognitive deficits. It is widely accepted that genetic and environmental factors contribute to the onset of schizophrenia. However, the etiology and pathology of the disease remain largely unexplored. Recently, the synaptopathology and the dysregulated synaptic plasticity and function have emerging as intriguing and prominent biological mechanisms of schizophrenia pathogenesis. Synaptic plasticity is the ability of neurons to change the strength of their connections in response to internal or external stimuli, which is essential for brain development and function, learning and memory, and vast majority of behavior responses relevant to psychiatric diseases including schizophrenia. Here, we reviewed molecular and cellular mechanisms of the multiple forms synaptic plasticity, and the functional regulations of schizophrenia-risk factors including disease susceptible genes and environmental alterations on synaptic plasticity and animal behavior. Recent genome-wide association studies have provided fruitful findings of hundreds of risk gene variances associated with schizophrenia, thus further clarifying the role of these disease-risk genes in synaptic transmission and plasticity will be beneficial to advance our understanding of schizophrenia pathology, as well as the molecular mechanism of synaptic plasticity.