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 (), which is developmentally regulated during adult-born neuron maturation. CRHR1 is a G-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 (). To elucidate the contributions of toward activity-dependent circuit remodeling, we targeted CRHR1 neurons in male and female mice for cell-type-specific manipulation of expression. Whereas loss of in CRHR1 neurons resulted in reduced dendritic complexity and decreased synaptic connectivity, overexpression of in CRHR1 neurons promoted dendritic outgrowth and branching and influenced synaptic function. Together, these findings suggest that the transcriptional program directed by downstream of local CRH signaling in adult-born neurons influences circuit dynamics in response to activity-dependent peptide signaling in the adult brain. Elucidating 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 factor We further show that is 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.

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Sensory stimulation leads to structural changes within the CNS (Central Nervous System), thus providing the fundamental mechanism for learning and memory. The olfactory circuit offers a unique model for studying experience-dependent plasticity, partly due to a continuous supply of integrating adult born neurons. Our lab has recently implemented an olfactory cued learning paradigm in which specific odor pairs are coupled to either a reward or punishment to study downstream circuit changes. The following protocol outlines the basic set up for our learning paradigm. Here, we describe the equipment setup, programming of software, and method of behavioral training.

PPP3CA encodes the catalytic subunit of calcineurin, a calcium‐calmodulin‐regulated serine–threonine phosphatase. Loss‐of‐function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain‐of‐function (GoF) variants in the auto‐inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26‐amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early‐onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.

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