α4βδ‐GABA_A receptors in dorsal hippocampal CA1 of adolescent female rats traffic to the plasma membrane of dendritic spines following voluntary exercise and contribute to protection of animals from activity‐based anorexia through localization at excitatory synapses

Abstract

In hippocampal CA1 of adolescent female rodents, α4βδ-GABA receptors (α4βδ-GABA Rs) suppress excitability of pyramidal neurons through shunting inhibition at excitatory synapses. This contributes to anxiolysis of stressed animals. Socially isolated adolescent female rats with 8 days of wheel access, the last 4 days of which entail restricted food access, have been shown to exhibit excessive exercise, choosing to run instead of eat (activity-based anorexia [ABA]). Upregulation of α4βδ-GABA Rs in the dorsal hippocampal CA1 (DH), seen among some ABA animals, correlates with suppression of excessive exercise. We used electron microscopic immunocytochemistry to show that exercise alone (EX), but not food restriction alone (FR), also augments α4βδ-GABA R expression at axospinous excitatory synapses of the DH (67%, P = 0.027), relative to socially isolated controls without exercise or food restriction (CON). Relative to CON, ABA animals' synaptic α4βδ-GABA R elevation was modestly elevated (37%), but this level correlated strongly and negatively with individual differences in ABA vulnerability-i.e., food restriction-evoked hyperactivity (Pearson R = -0.902, P = 0.002) and weight changes (R = 0.822, P = 0.012). These correlations were absent from FR and EX brains or ventral hippocampus of ABA brains. Comparison to CON of α4βδ-GABA R location in the DH indicated that ABA induces trafficking of α4βδ-GABA R from reserve pools in spine cytoplasm to excitatory synapses. Pair-housing CON animals reduced cytoplasmic α4βδ-GABA R without reducing synaptic α4βδ-GABA R. Thus, exercise induces trafficking of α4βδ-GABA Rs to excitatory synapses, while individual differences in ABA vulnerability are linked most strongly to trafficking of α4βδ-GABA Rs in the reverse direction-from excitatory synapses to the reserve pool during co-occurring food restriction. © 2017 Wiley Periodicals, Inc.

α4-GABAA receptors of hippocampal pyramidal neurons are associated with resilience against activity-based anorexia for adolescent female mice but not for males

“…Up-regulation of α4-subunits of GABA A Rs was previously shown to occur within the hippocampus of adolescent female ABA rats (Aoki et al, 2012; Aoki et al, 2014; Aoki et al, 2017) and mice (Wable et al, 2015a). However, none of those studies compared a4-immunoreactivity between the sexes.…”

“…At puberty onset, its expression in dorsal CA1 of female rodents increases transiently in response to the rapid rise, then the decline in the level of allopregnanolone (Shen et al, 2007; Aoki et al, 2012). ABA increases alpha4betadelta-GABA A R expression at excitatory synapses of stratum radiatum of dorsal hippocampal CA1 of adolescent female rodents (Aoki et al, 2012; Wable et al, 2015a; Aoki et al, 2017). However, whether ABA increases alpha4betadelta-GABA A R expression in adolescent males remained unknown.…”

Dendrites of the dorsal and ventral hippocampal CA1 pyramidal neurons of singly housed female rats exhibit lamina‐specific growths and retractions during adolescence that are responsive to pair housing

“…Adolescence is a period of psychiatric vulnerability which, in turn, is influenced by anxiety that is proposed to be regulated more by the ventral than the dorsal hippocampus (Bannerman et al, ; McHugh, Deacon, Rawlins, & Bannerman, ). However, we have data indicating otherwise (Aoki, Chen, Chowdhury, & Piper, ). It has also been shown that dorsal and ventral hippocampal lesions interact with puberty to result in different behavioral deficits in adulthood (Lipska, Jaskiw, & Weinberger, ; Pacteau, Einon, & Sinden, ).…”

Vulnerable and Resilient Phenotypes in a Mouse Model of Anorexia Nervosa

“…Vulnerability to AN might vary due to individual differences in any of these responses to caloric restriction, differences that could result from variation in dopamine genes or genes that modulate dopamine (e.g., leptin, insulin, ghrelin, glucocorticoid, orexin). Of course, factors independent of dopamine may also modulate vulnerability [e.g., (100)].…”