Summary Dendritic spines undergo actin-based growth and shrinkage during synaptic plasticity. The actin depolymerizing factor (ADF)/cofilin family of actin-associated proteins plays important roles in spine plasticity. Elevated ADF/cofilin activities often lead to reduced spine size and immature spine morphology, but can enhance synaptic potentiation in some cases. Therefore ADF/cofilin may exert distinct effects on postsynaptic structure and function. Here we report that ADF/cofilin-mediated actin dynamics regulate AMPA receptor (AMPAR) trafficking during synaptic potentiation, which is distinct from actin's structural role in spine morphology. We find that elevated ADF/cofilin activity markedly enhances surface addition of AMPARs after chemically-induced LTP (cLTP), whereas inhibition of ADF/cofilin abolishes AMPAR addition. Our data further show that cLTP elicits a temporal sequence of ADF/cofilin dephosphorylation and phosphorylation that underlies AMPAR trafficking and spine enlargement. These findings suggest a novel role for temporally-regulated ADF/cofilin activities in postsynaptic modifications of receptor number and spine size during synaptic plasticity.

Schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution.

Background: Cofilin rods are associated with Alzheimer disease, but their pathological significance is unclear. Results: Time-lapse imaging revealed that cofilin rods inhibit the movement of mitochondria and early endosomes. Cofilin rods reduce dendritic spines and impair synaptic transmission. Cofilin rods are discovered in senile rat brains. Conclusion: Cofilin rods block intracellular transport and induce synaptic loss. Significance: Our work identifies a signaling pathway underlying neurodegeneration and brain aging.

Parkinson's disease (PD) is a complex and highly variable neurodegenerative disease. Familial PD is caused by mutations in several genes with diverse and mostly unknown functions. It is unclear how dysregulation of these genes results in the relatively selective death of nigral dopaminergic neurons (DNs). To address this question, we modeled PD by knocking out the PD genes PARKIN (PRKN), DJ-1 (PARK7), and ATP13A2 (PARK9) in independent isogenic human pluripotent stem cell (hPSC) lines. We found increased levels of oxidative stress in all PD lines. Increased death of DNs upon differentiation was found only in the PARKIN knockout line. Using quantitative proteomics, we observed dysregulation of mitochondrial and lysosomal function in all of the lines, as well as common and distinct molecular defects caused by the different PD genes. Our results suggest that precise delineation of PD subtypes will require evaluation of molecular and clinical data.