NPAS4 in the medial prefrontal cortex mediates chronic social defeat stress-induced anhedonia-like behavior and reductions in excitatory synapses

Abstract

Chronic stress can produce reward system deficits (i.e., anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and it is required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation in the mice. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reductions in pyramidal neuron dendritic spine density, excitatory synaptic transmission, and presynaptic function, revealing a relationship between perturbation in excitatory synaptic transmission and the expression of anhedonia-like behavior in the mice. Finally, analysis of the mice mPFC tissues revealed that NPAS4 regulates the expression of numerous genes linked to glutamatergic synapses and ribosomal function, the expression of upregulated genes in CSDS-susceptible animals, and differentially expressed genes in postmortem human brains of patients with common neuropsychiatric disorders, including depression. Together, our findings position NPAS4 as a key mediator of chronic stress-induced hypofrontal states and anhedonia-like behavior.

Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

“…Furthermore, FRMPD3 is an NPAS4-regulated inhibitory neuronal gene, suggesting that the activity of FRMPD3 promotes the development of excitatory synaptic connections in somatostatin neurons [ 70 ]. Several studies have suggested that NPAS4 may regulate depression, anxiety, and neurocognitive disorders and play a critical role in the correlation between long-term stress and symptoms of depression [ 71 , 72 ]. Our analysis suggests that FRMPD3 is involved in synaptic formation and regulation, potentially influencing MDD development by modulating synaptic plasticity.…”

Daily light-induced transcription in visual cortex neurons drives downward Firing Rate Homeostasis and stabilizes sensory processing

“…Lastly, an important question is whether similar homeostatic mechanisms based on experience-induced transcription maintain the functional stability of neural circuits other than the visual cortex. Given that experience-induced gene transcription was observed in many neural circuits 33,34,36,[81][82][83][84][85] and that experiments e.g in the hippocampus, the prefrontal cortex and the somatosensory cortex revealed that early-induced TFs such as NPAS4 48,86,87 and FOS 65 and late-induced effectors such as ARC 88 , NARP 53 and BDNF 51 regulate specific sets of synapses and E/I-ratio according to a homeostatic circuit logic also in these neural circuits, it seems likely that this is indeed the case. We therefore propose that a generalizable function of activityinduced transcription in neural circuits lies in the activity-induced normalization of E/I-ratio and control over FRH to thereby counterbalance other forms of experience-dependent cellular-synaptic plasticity (e.g.…”

Integrative transcriptome- and DNA methylation analysis of brain tissue from the temporal pole in suicide decedents and their controls

“…In vivo studies in rodent models have shown that NPAS4 has a neuroprotective role in cerebral ischemia and epilepsy [ 54 ]. Other animal models have indicated that NPAS4 could have a role in fear memory, anxiety, social- and depressive-like behavior [ 55 ] and Npas4 knockout mice display social anxiety, hyperactivity, memory and learning deficits [ 49 , 56 , 57 ]. NPAS4 deficiency in mice results in an increase in activated microglia and astrocytes as well as increased protein levels of IL-6 and TNF-α after stroke [ 54 ].…”