Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus

Abstract

The interplay of environmental and genetic factors in the developmental organization of the hippocampus has not been fully elucidated. The neuropeptide corticotropin-releasing factor (CRF) is released from hippocampal interneurons by environmental signals, including stress, to increase synaptic efficacy. In the early postnatal hippocampus, we have previously characterized a transient population of CRF-expressing Cajal-Retzius-like cells. Here we queried whether this stress-activated neuromodulator influences connectivity in the developing hippocampal network. Using mice deficient in the principal hippocampal CRF receptor [CRF 1(؊͞؊)] and organotypic cultures grown in the presence of synthetic CRF, or CRF receptor antagonists, we found robust effects of CRF on dendritic differentiation in hippocampal neurons. In CRF 1(؊͞؊) mice, the dendritic trees of hippocampal principal cells were exuberant, an effect that was induced in normal hippocampi in vitro by the presence of CRF 1 antagonists. In both cases, total dendritic length and dendritic branching were significantly increased. In contrast, exogenous synthetic CRF blunted the dendritic growth in hippocampal organotypic cultures. Taken together, these findings suggest that endogenous CRF, if released excessively by previous early postnatal stress, might influence neuronal connectivity and thus function of the immature hippocampus.corticotropin-releasing hormone ͉ stress ͉ corticotropin-releasing factor receptor ͉ neuropeptide ͉ Cajal-Retzius cells T he developmental organization of the hippocampal network is a complex process, requiring the interplay of genetic and environmental factors. Establishment of basic hippocampal connectivity is governed by genetically determined mechanisms, including the coordinated activation of transcription factors (1-3), and the expression of both local and more generally acting guidance molecules (4-6). Once the basic elements are in place, refinement of connectivity is achieved through environmental stimuli that influence neuronal activity (7-9). Among the elements that contribute to developmental organization of the hippocampus are the Cajal-Retzius (CR) cells (10, 11). CR cells, found in hippocampal marginal zones, release reelin, an extracellular matrix protein required for layer formation and positioning of cortical neurons (12, 13). Because lack of reelin causes perturbation of cortical lamination (14), control of neuronal positioning has been considered the major function of CR cells. However, recent results suggest additional roles for CR cells that are independent of reelin (15-18).We have previously characterized a subset of CR cells that do not express reelin but release the neuropeptide corticotropinreleasing factor (CRF).ʈ CRF functions primarily as a regulator of the neuroendocrine stress response (19,20) but is also widely expressed within the central nervous system, where it acts as a neuromodulator (21)(22)(23)(24) 5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine, previously R121919} were 0.1 or 1 M (for G...

Cellular and molecular mechanisms of hippocampal activation by acute stress are age-dependent

“…Data for the general CRH receptor blocker resembled those for the selective CRF 1 antagonist, and are presented for the Fos expression only (Figure 4f). Taken together, these data indicate that activation of the CRF 1 receptor is required for stress-induced neuronal activation in immature hippocampus by central (likely hippocampal 59 ) CRH.…”

Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

“…CRH may exert these effects via altering signaling (CRHR2) or the glucocorticoid feedback (Fkbp5) during development. Importantly, early-life CRH hyper-signaling results in structural deficits (Chen et al, 2004), anxiogenic, and despair-like effects, which cannot be reproduced by adultonset CRHOE (Kolber et al, 2010;Toth et al, 2014). Here we show that these early-life stress effects are markedly modulated by sex, potentially via sex-specific compensatory mechanisms in response to CRH hyper-signaling.…”

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

“…CRH has potent effects on dendritic spines and synapse integrity, effects that are mediated via actin remodeling , calcium-dependent calpain activation and likely additional mechanisms. Chronic exposure to CRH may provoke dendritic stunting and atrophy (Chen et al, 2004b). Thus, abnormal, high levels of CRH may impair Figure 1.…”