Neural Abelson-related gene-binding protein 2 (nArgBP2) was originally identified as a protein that directly interacts with synapseassociated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3), a postsynaptic scaffolding protein critical for the assembly of glutamatergic synapses. Although genetic deletion of nArgBP2 in mice leads to manic/bipolar-like behaviors resembling many aspects of symptoms in patients with bipolar disorder, the actual function of nArgBP2 at the synapse is completely unknown. Here, we found that the knockdown (KD) of nArgBP2 by specific small hairpin RNAs (shRNAs) resulted in a dramatic change in dendritic spine morphology. Reintroducing shRNA-resistant nArgBP2 reversed these defects. In particular, nArgBP2 KD impaired spinesynapse formation such that excitatory synapses terminated mostly at dendritic shafts instead of spine heads in spiny neurons, although inhibitory synapse formation was not affected. nArgBP2 KD further caused a marked increase of actin cytoskeleton dynamics in spines, which was associated with increased Wiskott-Aldrich syndrome protein-family verprolin homologous protein 1 (WAVE1)/p21-activated kinase (PAK) phosphorylation and reduced activity of cofilin. These effects of nArgBP2 KD in spines were rescued by inhibiting PAK or activating cofilin combined with sequestration of WAVE. Together, our results suggest that nArgBP2 functions to regulate spine morphogenesis and subsequent spine-synapse formation at glutamatergic synapses. They also raise the possibility that the aberrant regulation of synaptic actin filaments caused by reduced nArgBP2 expression may contribute to the manifestation of the synaptic dysfunction observed in manic/bipolar disorder. nArgBP2 | dendritic spines | excitatory synapse | actin | bipolar disorder T he postsynaptic enriched adaptor protein neural Abelsonrelated gene-binding protein 2 (nArgBP2), a neural-specific splice variant of the ubiquitous ArgBP2, was originally identified as a binding partner of synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3) (1). It belongs to a family of adaptor proteins that are involved in the regulation of cell adhesion, actin cytoskeleton organization, and growth factor receptor signaling (2). This protein family is characterized by a sorbin homology (SoHo) domain in the NH 2 -terminal region and three Src homology 3 (SH3) domains in the COOH-terminal region (3). Although the SoHo domain remains poorly characterized, the SH3 domains bind signaling protein kinases, the ubiquitin ligase, and protein involved in the regulation of focal adhesions and adhering junctions (1, 4-6). The NH 2 -terminal region of nArgBP2, which contains the SoHo domain, interacts with spectrin, whereas the COOH-terminal SH3 domains bind dynamin, synaptojanin, Wiskott-Aldrich syndrome protein-family verprolin homologous protein (WAVE) isoforms, and WAVE regulatory proteins (3), all of which participate in the regulation of the actin cytoskeleton. We also found that the down-re...

Neuron–microglia interactions have a crucial role in maintaining the neuroimmune system. The balance of neuroimmune system has emerged as an important process in the pathophysiology of depression. However, how neuron–microglia interactions contribute to major depressive disorders has been poorly understood. Herein, we demonstrated that microglia-derived synaptic changes induced antidepressive-like behavior by using microglia-specific signal transducer and activator of transcription 3 (STAT3) knockout (KO) (STAT3fl/fl;LysM-Cre+/−) mice. We found that microglia-specific STAT3 KO mice showed antidepressive-like behavior in the forced swim, tail suspension, sucrose preference, and open-field tests. Surprisingly, the secretion of macrophage colony-stimulating factor (M-CSF) was increased from neuronal cells in the brains of STAT3fl/fl;LysM-Cre+/− mice. Moreover, the phosphorylation of antidepressant-targeting mediators and brain-derived neurotrophic factor expression were increased in the brains of STAT3fl/fl;LysM-Cre+/− mice as well as in neuronal cells in response to M-CSF stimulation. Importantly, the miniature excitatory postsynaptic current frequency in the medial prefrontal cortex was increased in STAT3fl/fl;LysM-Cre+/− mice and in the M-CSF treatment group. Collectively, microglial STAT3 regulates depression-related behaviors via neuronal M-CSF-mediated synaptic activity, suggesting that inhibition of microglial STAT3 might be a new therapeutic strategy for depression.

Background: Calcyon has been associated with various dopamine D 1 receptor signalings despite no direct interaction between them. Results: Calcyon forms a novel ternary complex with D 1 DR through PSD-95. Conclusion: Calcyon, by forming a ternary complex, regulates D 1 DR internalization in a phosphorylation-dependent manner. Significance: Regulation of dopaminergic signaling by calcyon⅐PSD-95⅐D 1 DR complex may represent a novel target for related neuropsychiatric disorders.

Emotional memory processing engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network are unclear. Here, we illustrate that synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Transcriptome analyses revealed that PC-specific STAT3 knockout (STAT3PKO) results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber (PF) to PC synapses was larger in STAT3PKO mice than in wild-type (WT) littermates. Fear conditioning induced long-term depression of PF–PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in WT littermates. STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory.