Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss

Abstract

Stress impairs cognition via corticotropin-releasing hormone receptor 1 (CRHR1), but the molecular link between abnormal CRHR1 signaling and stress-induced cognitive impairments remains unclear. We investigated whether the cell adhesion molecule nectin-3 is required for the effects of CRHR1 on cognition and structural remodeling after early-life stress exposure. Postnatally stressed adult mice had decreased hippocampal nectin-3 levels, which could be attenuated by CRHR1 inactivation and mimicked by corticotropin-releasing hormone (CRH) overexpression in forebrain neurons. Acute stress dynamically reduced hippocampal nectin-3 levels, which involved CRH-CRHR1, but not glucocorticoid receptor, signaling. Suppression of hippocampal nectin-3 caused spatial memory deficits and dendritic spine loss, whereas enhancing hippocampal nectin-3 expression rescued the detrimental effects of early-life stress on memory and spine density in adulthood. Our findings suggest that hippocampal nectin-3 is necessary for the effects of stress on memory and structural plasticity and indicate that the CRH-CRHR1 system interacts with the nectin-afadin complex to mediate such effects.

Stress during a Critical Postnatal Period Induces Region-Specific Structural Abnormalities and Dysfunction of the Prefrontal Cortex via CRF1

“…Once the stressor is perceived, CRF is rapidly released and activates CRF 1 that, in turn, interacts with neurotransmitter systems and synaptic molecules to modulate neural circuit development and synaptic plasticity (Andres et al, 2013;Tan et al, 2004;Wang et al, 2013). Using the same stress paradigm, we and others have demonstrated the critical role of the CRF-CRF 1 system in mediating the effects of earlylife stress on the development, plasticity, and function of the hippocampus.…”

“…Intriguingly, the protein levels of PKC isoforms increase rapidly around the first postnatal week (Roisin and Barbin, 1997). In future studies, the involvement of PKC and other candidate molecules, including nectin-3 that interacts with CRF 1 to modulate the negative stress effects on hippocampal plasticity (Wang et al, 2013) as well as glucocorticoids and glutamate receptors, in postnatal stress-induced prefrontal dysfunction should be determined.…”

“…The total distance traveled, number of arm entries, spontaneous alternation ratio (Wang et al, 2013), and same arm return ratio (Wall and Messier, 2002;Wietrzych et al, 2005) were measured.…”

“…Recently, we and others reported the crucial role of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF 1 ) in modulating the negative effects of early-life stress on the development and plasticity of the hippocampus (Ivy et al, 2010;Liao et al, 2014;Wang et al, 2011;Wang et al, 2013). Because CRF-and CRF 1 -expressing neurons are found in mPFC (Alon et al, 2009;Kühne et al, 2012), this system may also modulate the effects of early-life stress on the development of mPFC pyramidal neurons and prefrontal function.…”

Hippocampal gene expression induced by cold swim stress depends on sex and handling

“…Another key regulator of gene expression following stress is corticotropin-releasing hormone (Crh) (Joëls and Baram, 2009). When acting through Crh receptor 1 (Crhr1), it mediates several of the rapid effects of acute stress in the hippocampus (Wang et al, 2013). Sex-differences in stress-induced gene regulation may therefore be due to differential responsiveness of the Crh system between sexes (Bangasser et al, 2010;Iwasaki-Sekino et al, 2009).…”