Npas4 Regulates a Transcriptional Program in CA3 Required for Contextual Memory Formation

Abstract

The rapid encoding of contextual memory requires the CA3 region of hippocampus, but the necessary genetic pathways remain unclear. We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning. Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice. By recruiting RNA polymerase II to promoters and enhancers of target genes, Npas4 regulates a learning-specific transcriptional program in CA3 that includes many well-known activity-regulated genes, suggesting that Npas4 is a master regulator of activity-regulated gene programs and is central to memory formation.

[P3–175]: Crtc1 Function During Memory Encoding Is Disrupted in Neurodegeneration

“…during memory consolidation (31), which is consistent with a role of this circuit in associating contextual cues with aversive events (11,12). Based on these results, we suggest that CRTC1 participates in transcriptional events mediating contextual memory in the dorsal hippocampus, a region required for contextual memory encoding (15,54).…”

Neuronal Per Arnt Sim (PAS) Domain Protein 4 (NPAS4) Regulates Neurite Outgrowth and Phosphorylation of Synapsin I

“…In our study, a ChIP assay showed that Npas4 binds the promoter of NeuN in Neuro2a cells. Accordingly, NPAS4 may have indirect effects through the regulation of other transcriptional factors (18). Taking these findings together, it is suggested that NPAS4 contributes to neurite development and functional maturation of neurons through the transcriptional regulation of neurotransmission and neurodevelopment-associated molecules.…”

“…A recent study demonstrated that the activity-dependent expression of NPAS4 regulates a transcriptional program in the CA3 hippocampus required for contextual memory formation (18).…”

“…We previously reported that reduced Npas4 mRNA levels may contribute to impairments in adult neurogenesis in the hippocampus, memory and emotional behaviors induced by social isolation or restriction stress (16,17). Recent studies (18,19) revealed that NPAS4 is important in memory formation and consolidation. Synaptic remodeling is considered to be a way for neurons to adapt cellular and neuronal circuits to environmental changes (20), and neurite arborization and rewiring may contribute to the neuronal plasticity in the brain (21)(22)(23)(24).…”

Inositol polyphosphate multikinase is a transcriptional coactivator required for immediate early gene induction

“…In the brain, IEG induction mediates the plasticity underlying complex processes such as learning, memory, and behavior (6)(7)(8). Thus, genetic deletion of these IEGs often leads to deficits in the encoding and consolidation of longterm memory (9)(10)(11). Signaling cascades in which neural activity induces IEGs have been elusive.…”