Hyper-diversity of CRH interneurons in mouse hippocampus

Abstract

Hippocampal inhibitory interneurons comprise an anatomically, neurochemically and electrophysiologically diverse population of cells that are essential for the generation of the oscillatory activity underlying hippocampal spatial and episodic memory processes. Here, we aimed to characterize a population of interneurons that express the stress-related neuropeptide corticotropin-releasing hormone (CRH) within existing interneuronal categories through the use of combined electrophysiological and immunocytochemical approaches. Focusing on CA1 strata pyramidale and radiatum of mouse hippocampus, CRH interneurons were found to exhibit a heterogeneous neurochemical phenotype with parvalbumin, cholecystokinin and calretinin co-expression observed to varying degrees. In contrast, CRH and somatostatin were never co-expressed. Electrophysiological categorization identified heterogeneous firing pattern of CRH neurons, with two distinct subtypes within stratum pyramidale and stratum radiatum. Together, these findings indicate that CRH-expressing interneurons do not segregate into any single distinct subtype of interneuron using conventional criteria. Rather our findings suggest that CRH is likely co-expressed in subpopulations of previously described hippocampal interneurons. In addition, the observed heterogeneity suggests that distinct CRH interneuron subtypes may have specific functional roles in the both physiological and pathophysiological hippocampal processes.

Deletion of CRH From GABAergic Forebrain Neurons Promotes Stress Resilience and Dampens Stress-Induced Changes in Neuronal Activity

“…Moreover, we addressed whether Crh CKO–GABA mice would display differential behaviors under baseline and chronic stress conditions. Mapping analyses in Crh CKO–GABA mice showed complete lack of Crh mRNA in the CeA, BNST, hippocampus and throughout most of the cortex, which is in line with previous studies reporting predominant expression of cortical and limbic CRH in GABAergic neurons (Chen et al, 1998, 2001; Kubota et al, 2011; Kubota, 2013; Dedic et al, 2018a; Gunn et al, 2019). To our initial surprise, Crh CKO–GABA mice showed no gross behavioral changes in locomotion, anxiety, startle response and fear memory, but exhibited social deficits under baseline conditions.…”

“…Using sensitive in situ hybridization (ISH) methods, we recently mapped the neurochemical identity of Crh neurons across the mouse brain, revealing an overwhelming majority of GABAergic ( Gad65/67 -positive) CRH neurons in the cortex, hippocampus, central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST), which has also been reported by others (Kubota et al, 2011; Kubota, 2013; Dedic et al, 2018a; Gunn et al, 2019). In contrast, Crh neurons in the Pir and PVN primarily coexpressed the glutamatergic markers Vglut1 and Vglut2 , respectively (Dedic et al, 2018a).…”

“…We and others have shown that CRHR1 is expressed in forebrain glutamatergic and GABAergic neurons, dopaminergic neurons of the ventral tegmental area (VTA) as well as a limited subset of serotonergic neurons of the dorsal raphe nucleus (Van Pett et al, 2000; Refojo et al, 2011). In contrast, cortical and limbic CRH expression is largely confined to GABAergic neurons with the exception of the piriform cortex (Pir) and PVN, where CRH is found in glutamatergic cells (Chen et al, 2001; Kubota et al, 2011; Dabrowska et al, 2013; Kubota, 2013; Dedic et al, 2018a; Gunn et al, 2019). Although it is well established that CRH/CRHR1 signaling mediates aversive responses, including anxiety and depression-like behaviors, several recent studies have challenged this viewpoint by revealing anxiolytic and appetitive properties of specific CRH/CRHR1 circuits.…”

Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity

“…During development, both glucocorticoids and CRH may directly inhibit dendritic arborization [28,34]. CRH is expressed in the hippocampus within a subpopulation of interneurons [35][36][37][38][39][40]. Both tonically [41] and during stress, CRH is released locally and binds to corticotropin releasing hormone type-1 (CRHR1) receptors on pyramidal cells [42], resulting in neuronal activation [41][42][43].…”

Short-term block of CRH receptor in adults mitigates age-related memory impairments provoked by early-life adversity

“…Reduction in hippocampal dendrites is associated with chronic increases in corticotropin releasing hormone (CRH) (Chen et al, 2013;Maras & Baram, 2012). CRH is expressed in the hippocampus within a subpopulation of interneurons (Chen et al, 2004;Chen, Bender, Frotscher, & Baram, 2001;Gunn, Sanchez, Lynch, Baram, & Chen, 2019;Hooper, Fuller, & Maguire, 2018;Hooper & Maguire, 2016;Yan, Toth, Schultz, Ribak, & Baram, 1998) and binds to corticotropin releasing hormone receptor type -1 (CRHR1) receptors on pyramidal cells, resulting in neuronal activation immediately following stress (Chen, Brunson, Müller, Cariaga, & Baram, 2000). Sustained increases in CRH binding to CRHR1 in the hippocampus results in reduced dendritic spines and synapse integrity via actin remodeling (Chen, Dube, Rice, & Baram, 2008;Chen et al, 2013Chen et al, , 2010, which results in deficits in learning and memory (Kim & Diamond, 2002;McEwen, 1999).…”