Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase

Abstract

Stressor exposure induces neuronal remodeling in specific brain regions. Given the persistence of stress-related illnesses, key next steps in determining the contributions of neural structure to mental health are to identify cell types that fail to recover from stressor exposure and to identify “trigger points” and molecular underpinnings of stress-related neural degeneration. We evaluated dendrite arbor structure on hippocampal CA1 pyramidal neurons before, during, and following prolonged exposure to one key mediator of the stress response – corticosterone (cortisol in humans). Basal dendrite arbors progressively simplified during a 3-week exposure period, and failed to recover when corticosterone was withdrawn. Corticosterone exposure decreased levels of the dendrite stabilization factor Abl2/Arg nonreceptor tyrosine kinase and phosphorylation of its substrates p190RhoGAP and cortactin within 11 days, suggesting that disruption of Arg-mediated signaling may trigger dendrite arbor atrophy and, potentially, behavioral abnormalities resulting from corticosterone exposure. To test this, we administered the novel, bioactive Arg kinase activator, 5-(1,3-diaryl-1H-pyrazol-4-yl)hydantoin, 5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2,4-imidazolidinedione (DPH), in conjunction with corticosterone. We found that repeated treatment corrected CA1 arbor structure, otherwise simplified by corticosterone. DPH also corrected corticosterone-induced errors in a hippocampal-dependent reversal learning task and anhedoniclike behavior. Thus, pharmacological compounds that target cytoskeletal regulators, rather than classical neurotransmitter systems, may interfere with stress-associated cognitive decline and mental health concerns.

Prefrontal cortical trkB, glucocorticoids, and their interactions in stress and developmental contexts

“…Activity-dependent neurotrophin signaling is generally thought to strengthen and help maintain active synapses by activating spine stabilization pathways. These pathways are also targeted by glucocorticoids, which are necessary for spine development and maintenance (Liston et al, 2013; Haditsch et al, 2009; Shapiro et al, 2017b). However, chronic stress or excess glucocorticoid levels lead to dendritic spine loss, at least in part, by GR-mediated disruption of the molecular mechanisms that stabilize spines.…”

Adolescent Corticosterone and TrkB Pharmaco-Manipulations Sex-Dependently Impact Instrumental Reversal Learning Later in Life

“…Indeed, under conditions of chronic stress in adult rats, stress-induced release of norepinephrine in the mPFC impairs certain forms of behavioral flexibility, while noradrenergic receptor blockade in the mPFC prevents stress-induced deficits (Jett and Morilak, 2013 ). On the other hand, 3 weeks of CORT exposure in adolescent male mice causes errors in a similar instrumental reversal task (Shapiro et al, 2017a ), indicating that males are not entirely resilient to CORT.…”

Gut microbiome partially mediates and coordinates the effects of genetics on anxiety-like behavior in Collaborative Cross mice

“…Our screen identified 62 genes known to be associated with anxiety, behavioral alterations and neurodevelopment of which 40 genes show expression in the brain based on in situ hybridization data from the Mouse Brain Atlas (Allen Brain Atlas) ( Table S4). For instance, allele variants of NTRK3, PPP2R2B, and ESR1 were associated with anxiety in humans [32][33][34] , knock-out mice of Cacna1h, Rapgef2, Clstn2, and Tnr exhibited abnormal anxiety-like behaviors [35][36][37][38] , and Isl1, Abl2, Dlgap1 and Csmd2 knock-out mice showed alterations in neurodevelopment and behavior [39][40][41][42] . In addition to these 62 known genes, our screen identified 79 genes not previously associated with anxiety, which includes 38 genes that show expression in the brain based on in situ hybridization data from the Mouse Brain Atlas (Allen Brain Atlas) ( Table S4).…”