Zepeda, J. C. | Search bioRxiv

bioRxiv2025

Photoperiodic Regulation of SK Channels in Dorsal Raphe Serotonin Neurons

Day length, or seasonal photoperiod, shapes mood and affective behaviors but the neural mechanisms underlying these effects are still being defined. Serotonin neurons of the dorsal raphe nucleus (DRN) are critical regulators of affective behaviors and photoperiod modulates their excitability and ongoing activity. Here, we investigated the influence of seasonal photoperiod on the function and expression of small conductance calcium-activated potassium (SK) channels which mediate the afterhyperpolarizing potential (AHP) in dorsal raphe serotonin neurons. Building on previous work demonstrating that photoperiod modulates serotonergic excitability and behavior, we hypothesized that day length influences SK channel activity, thereby contributing to differences in neuronal excitability observed between Long, Equinox, and Short photoperiod conditions. Using multi-electrode array recording of DRN slices we found a significant dose-dependent increase in spike rate to the application of the SK channel inhibitor apamin, indicating that SK channels indeed influence the spike rate of dorsal raphe serotonin neurons. In addition, DRN neurons in slices from Long photoperiod mice exhibited less pronounced responses to apamin relative to those from Short photoperiod mice, suggesting reduced function or expression of SK channels in Long photoperiod. Indeed, whole-cell recordings demonstrated that SK channel-mediated AHP currents were reduced in Long photoperiod mice. However, there were no significant differences in expression levels of the SK3 subunit (Kcnn3) in DRN serotonin neurons across photoperiod conditions as determined by single molecule fluorescence in situ hybridization. Overall, these findings indicate that photoperiod modulates SK channel function in DRN serotonin neurons likely at a post-transcriptional level. This study advances our understanding of how seasonal cues influence intrinsic neuronal properties and provides a mechanistic link between photoperiod, serotonergic excitability, and mood-related behaviors. The identification of SK channels as modulators of photoperiodic effects may offer novel therapeutic targets for mood disorders associated with dysregulated serotonin signaling.

neuroscience↗

bioRxiv2024

The noncoding circular RNA circHomer1 regulates developmental experience-dependent plasticity in mouse visual cortex

Circular RNAs (circRNAs) are a class of closed-loop, single stranded RNAs whose expression is particularly enriched in the brain. Despite this enrichment and evidence that the expression of circRNAs are altered by synaptic development and in response to synaptic plasticity in vitro, the regulation by and function of the majority of circRNAs in experience-dependent plasticity in vivo remain unexplored. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of experience-dependent developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent mRNA forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following 3-day MD. Knockdown of circHomer1 delayed the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown also led to a reduction in average dendritic spine size prior to MD but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 knockdown impairs experience-dependent AMPA receptor endocytosis. Thus, the expression of multiple circRNAs are regulated by experience-dependent developmental plasticity, and our findings highlight the essential role of circHomer1 in V1 synaptic development and experience-dependent plasticity. Significance StatementCircular RNAs (circRNAs) are a class of closed-loop RNAs formed through back-splicing of exon and/or intron junctions. Initially considered as byproducts of aberrant RNA splicing with limited function, recent studies have implicated circRNAs in various neurological disorders. Despite their abundant expression in the brain, the role of circRNAs in experience-dependent plasticity remains poorly understood. We conducted an in vivo transcriptome analysis of circRNAs whose expression was regulated by experience-dependent plasticity in the mouse visual cortex and highlight circHomer1, a circRNA derived from the Homer1 gene, as a circRNA critical for synaptic development and experience-dependent plasticity in vivo.

neuroscience↗