POU6f1 Mediates Neuropeptide-Dependent Plasticity in the Adult Brain

• DOI: 10.1523/jneurosci.1641-17.2017
• Publication Date: 2018-01-05T18:30:39Z
• Authors: Cynthia K. McClard; Mikhail Y. Kochukov; Isabella Herman; Zhandong Liu; Aiden Eblimit; Yalda Moayedi; Joshua Ortiz-Guzman; Daniel Colchado; Brandon Pekarek; Sugi Panneerselvam; Graeme Mardon; Benjamin R. Arenkiel
• Keywords: Male; Mice, Knockout; Neurons; 0301 basic medicine; Neuronal Plasticity; Behavior, Animal; Corticotropin-Releasing Hormone; Neuropeptides; Brain; Olfactory Bulb; Receptors, Corticotropin-Releasing Hormone; Smell; Mice; 03 medical and health sciences; Animals; Female; Gene Knock-In Techniques; Octamer Transcription Factor-3

The mouse olfactory bulb (OB) features continued, activity-dependent integration of adult-born neurons, providing a robust model with which to examine mechanisms of plasticity in the adult brain. We previously reported that local OB interneurons secrete the neuropeptide corticotropin-releasing hormone (CRH) in an activity-dependent manner onto adult-born granule neurons and that local CRH signaling promotes expression of synaptic machinery in the bulb. This effect is mediated via activation of the CRH receptor 1 (CRHR1), which is developmentally regulated during adult-born neuron maturation. CRHR1 is a GS-protein-coupled receptor that activates CREB-dependent transcription in the presence of CRH. Therefore, we hypothesized that locally secreted CRH activates CRHR1 to initiate circuit plasticity programs. To identify such programs, we profiled gene expression changes associated with CRHR1 activity in adult-born neurons of the OB. Here, we show that CRHR1 activity influences expression of the brain-specific Homeobox-containing transcription factor POU Class 6 Homeobox 1 (POU6f1). To elucidate the contributions ofPOU6f1toward activity-dependent circuit remodeling, we targeted CRHR1+neurons in male and female mice for cell-type-specific manipulation ofPOU6f1expression. Whereas loss ofPOU6f1in CRHR1+neurons resulted in reduced dendritic complexity and decreased synaptic connectivity, overexpression ofPOU6f1in CRHR1+neurons promoted dendritic outgrowth and branching and influenced synaptic function. Together, these findings suggest that the transcriptional program directed byPOU6f1downstream of local CRH signaling in adult-born neurons influences circuit dynamics in response to activity-dependent peptide signaling in the adult brain.SIGNIFICANCE STATEMENTElucidating mechanisms of plasticity in the adult brain is helpful for devising strategies to understand and treat neurodegeneration. Circuit plasticity in the adult mouse olfactory bulb is exemplified by both continued cell integration and synaptogenesis. We previously reported that these processes are influenced by local neuropeptide signaling in an activity-dependent manner. Here, we show that local corticotropin-releasing hormone (CRH) signaling induces dynamic gene expression changes in CRH receptor expressing adult-born neurons, including altered expression of the transcription factorPOU6f1. We further show thatPOU6f1is necessary for proper dendrite specification and patterning, as well as synapse development and function in adult-born neurons. Together, these findings reveal a novel mechanism by which peptide signaling modulates adult brain circuit plasticity.