MODULATION OF NEURONAL ACTIVITY-DEPENDENT GENE EXPRESSION BY CAMP RESPONSE ELEMENT MODULATOR (<EM>CREM</EM>) ISOFORMS

Neuronal activity-dependent gene transcription is a fundamental mechanism supporting long-lasting changes in synaptic function in response to specific neuronal activity patterns. Among the activity-dependent transcriptional regulators involved in this process, the CREB/CRTC1 signaling pathway plays a central role in coupling synaptic stimulation to nuclear gene expression. Interestingly, different members of the CREB family of transcription factors contain cAMP response element (CRE) sequences in their gene promoters, thus comprising CREB target genes themself, such as the cAMP response element modulator (CREM) gene. One notable isoform of CREM is the inducible cAMP early repressor (ICER), which lacks transactivation domains, thus repressing gene expression by competitively occupying CRE sites and displacing CREB. In this study, we investigated the transcriptional regulation of specific CREM/ICER isoforms in primary mouse cortical neurons in response to neuronal activity and CREB modulation. Neuronal stimulation with forskolin and potassium chloride (FSK/KCl) induced a time-dependent increase in Crem activator (τ), repressor (α), and inducible repressor (Icer) transcripts, consistent with activity-dependent transcription. Manipulation of CREB levels revealed differential regulation of Crem isoforms, with CREB preferentially promoting Icer expression. Moreover, modulation of ICER impacts the expression of CREB target genes, suggesting that ICER functions as a negative regulator to fine-tune the activity-dependent transcriptional programs regulated by CREB/CRTC1 signaling. Our findings underscore the role of ICER in activity-dependent transcription, which could be useful for therapeutic strategies targeting synaptic and cognitive functions.