a4bd-GABAA 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

In hippocampal CA1 of adolescent female rodents, a4bdGABAA receptors (a4bd-GABAARs) 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 a4bdGABAARs 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 a4bdGABAAR expression at axospinous excitatory synapses of the DH (67%, P50.027), relative to socially isolated controls without exercise or food restriction (CON). Relative to CON, ABA animals’ synaptic a4bd-GABAAR 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 R520.902, P5 0.002) and weight changes (R5 0.822, P50.012). These correlations were absent from FR and EX brains or ventral hippocampus of ABA brains. Comparison to CON of a4bd-GABAAR location in the DH indicated that ABA induces trafficking of a4bd-GABAAR from reserve pools in spine cytoplasm to excitatory synapses. Pair-housing CON animals reduced cytoplasmic a4bd-GABAAR without reducing synaptic a4bd-GABAAR. Thus, exercise induces trafficking of a4bd-GABAARs to excitatory synapses, while individual differences in ABA vulnerability are linked most strongly to trafficking of a4bd-GABAARs in the reverse direction—