α4βδ-GABAARs in the hippocampal CA1 as a biomarker for resilience to activity-based anorexia

Abstract

Anorexia nervosa (AN) is a psychiatric illness characterized by restricted eating and an intense fear of gaining weight. Most individuals with AN are females, diagnosed first during adolescence, 40% to 80% of whom exhibit excessive exercise, and an equally high number with a history of anxiety disorder. We sought to determine the cellular basis for individual differences in AN vulnerability by using an animal model, activity-based anorexia (ABA), that is induced by combining food restriction (FR) with access to a running wheel that allows voluntary exercise. Previously, we showed that by the 4th day of FR, the ABA group of adolescent female rats exhibit > 500% greater levels of non-synaptic α4βδ−GABAARs at the plasma membrane of hippocampal CA1 pyramidal cell spines, relative to the levels found in age-matched controls that are not FR and without wheel access. Here, we show that the ABA group exhibits individual differences in body weight loss, with some losing nearly 30%, while others lose only 15%. The individual differences in weight loss are ascribable to individual differences in wheel activity that both precedes and concurs with days of FR. Moreover, the increase in activity during FR correlates strongly and negatively with α4βδ−GABAAR levels (R= - 0.9, p<0.01). This negative correlation is evident within 2 days of FR, before body weight loss approaches life-threatening levels for any individual. These findings suggest that increased shunting inhibition by α4βδ−GABAARs in spines of CA1 pyramidal neurons may participate in the protection against the ABA-inducing environmental factors of severe weight loss by suppressing excitability of the CA1 pyramidal neurons which, in turn, is related indirectly to suppression of excessive exercise. The data also indicate that, although exercise has many health benefits, it can be maladaptive to individuals with low levels of α4βδ−GABAARs in the CA1, particularly when combined with FR.

NR2A- and NR2B-NMDA receptors and drebrin within postsynaptic spines of the hippocampus correlate with hunger-evoked exercise

“…Spine membrane levels of extra-synaptic α4βδ-containing GABA A Rs, which mediate shunting inhibition at dendritic spines of stratum radiatum of the dorsal CA1 (Shen et al 2007), correlate strongly and negatively with the distances run by ABA animals (Aoki et al 2014). Importantly, these α4βδ-GABA A Rs are inactivated by allopregnanolone in a chloride ion-flux-dependent manner, a condition brought on in the dorsal CA1 of adolescent females when an animal is stressed (Shen et al 2007).…”

“…ABA is induced readily in wild-type rodents by imposing food restriction in combination with access to a running wheel (Aoki et al 2014; Wable et al 2015b). This is an important behavior shared among individuals with AN (Davis et al 1997), with some studies indicating that all patients exhibit hyperactivity/over-exercise during the course of the illness and/or prior to diagnosis (Kron et al 1978).…”

“…While capturing the above symptoms of AN, ABA also reveals individual differences in vulnerability, quantified as the extent of food-restriction-evoked hyperactivity and weight loss (Aoki et al 2014; Chen et al 2016; Chowdhury et al 2013; Wable et al 2015a, b; Nedelescu et al 2016). Since excitability of the hippocampus is strongly linked to stress-induced anxiety (Shen et al 2007), and the extent of food-restriction-evoked anxiety is correlated with wheel running (Wable et al 2015b), we hypothesized that individual differences in wheel running might be influenced by the excitability of hippocampal neurons.…”

Synaptic changes in the hippocampus of adolescent female rodents associated with resilience to anxiety and suppression of food restriction-evoked hyperactivity in an animal model for anorexia nervosa

“…Moreover, there was, again, a strong correlation between the animal’s FR-evoked running and the level of α4βδ-GABA A Rs at spine membranes immediately adjacent to excitatory axo-spinous synapses (Fig. 2B in (Aoki et al, 2014b), with the most resilient animals having the most increased levels of α4βδ-GABA A R. When examined after only 2 days of FR, we, again, observed a strong correlation between α4βδ-GABA A R levels and the extent of the animal’s suppression of FR-evoked running. However, approximately half of the α4βδ-GABA A Rs resided in the spine cytoplasm, rather than at the plasma membrane (Fig.…”

“…Analysis of the hippocampus immediately at the end of the first ABA (after 4 days of FR) (Aoki et al, 2014b) revealed that some animals expressed levels of α4βδ-GABA A Rs that were nearly five-fold those of controls, while others exhibited levels no different from controls. Moreover, there was, again, a strong correlation between the animal’s FR-evoked running and the level of α4βδ-GABA A Rs at spine membranes immediately adjacent to excitatory axo-spinous synapses (Fig.…”