Many symptoms induced by isolation rearing of rodents may be relevant to neuropsychiatric disorders, including depression. However, identities of transcription factors that regulate gene expression in response to chronic social isolation stress remain elusive. The transcription factor ATF‐7 is structurally related to ATF‐2, which is activated by various stresses, including inflammatory cytokines. Here, we report that Atf‐7‐deficient mice exhibit abnormal behaviours and increased 5‐HT receptor 5B (Htr5b) mRNA levels in the dorsal raphe nuclei. ATF‐7 silences the transcription of Htr5B by directly binding to its 5′‐regulatory region, and mediates histone H3‐K9 trimethylation via interaction with the ESET histone methyltransferase. Isolation‐reared wild‐type (WT) mice exhibit abnormal behaviours that resemble those of Atf‐7‐deficient mice. Upon social isolation stress, ATF‐7 in the dorsal raphe nucleus is phosphorylated via p38 and is released from the Htr5b promoter, leading to the upregulation of Htr5b. Thus, ATF‐7 may have a critical role in gene expression induced by social isolation stress.

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Classical studies have shown that neuronal immediate-early genes (IEGs) play important roles in synaptic processes critical for key brain functions. IEGs are transiently activated and rapidly upregulated in discrete neurons in response to a wide variety of cellular stimuli, and they are uniquely involved in various aspects of synapse development. In this review, we summarize recent studies of a subset of neuronal IEGs in regulating synapse formation, transmission, and plasticity. We also discuss how the dysregulation of neuronal IEGs is associated with the onset of various brain disorders and pinpoint key outstanding questions that should be addressed in this field.

Neurotrophin-3 (NT-3) is a secreted neurotrophic factor that binds neurotrophin receptor tyrosine kinase C (TrkC), which in turn binds to presynaptic protein tyrosine phosphatase (PTP) to govern excitatory synapse development. However, whether and how NT-3 cooperates with the TrkC-PTP synaptic adhesion pathway and TrkC-mediated intracellular signaling pathways in rat cultured neurons has remained unclear. Here, we report that NT-3 enhances TrkC binding affinity for PTP. Strikingly, NT-3 treatment bidirectionally regulates the synaptogenic activity of TrkC: at concentrations of 10 -25 ng/ml, NT-3 further enhanced the increase in synapse density induced by TrkC overexpression, whereas at higher concentrations, NT-3 abrogated TrkC-induced increases in synapse density. Semiquantitative immunoblotting and optogenetics-based imaging showed that 25 ng/ml NT-3 or light stimulation at a power that produced a comparable level of NT-3 (6.25 W) activated only extracellular signal-regulated kinase (ERK) and Akt, whereas 100 ng/ml NT-3 (light intensity, 25 W) further triggered the activation of phospholipase C-␥1 and CREB independently of PTP. Notably, disruption of TrkC intracellular signaling pathways, extracellular ligand binding, or kinase activity by point mutations compromised TrkC-induced increases in synapse density. Furthermore, only sparse, but not global, TrkC knock-down in cultured rat neurons significantly decreased synapse density, suggesting that intercellular differences in TrkC expression level are critical for its synapse-promoting action. Together, our data demonstrate that NT-3 is a key factor in excitatory synapse development that may direct higher-order assembly of the TrkC/ PTP complex and activate distinct intracellular signaling cascades in a concentration-dependent manner to promote competitionbased synapse development processes.

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