α4Bδ GABAA RECEPTORS REDUCE DENDRITIC SPINE DENSITY IN CA1 HIPPOCAMPUS AND IMPAIR RELEARNING ABILITY OF ADOLESCENT FEMALE MICE: EFFECTS OF A GABA AGONIST AND A STRESS STEROID

Synaptic pruning underlies the transition from an immature to an adult CNS through refinements of neuronal circuits. Our recent study indicates that pubertal synaptic pruning is triggered by the inhibition generated by extrasynaptic alpha 4 beta delta GABA(A) receptors (GABARs) which are increased for 10 d on dendritic spines of CA1 pyramidal cells at the onset of puberty (PND 35-44) in the female mouse, suggesting alpha 4 beta delta GABARs as a novel target for the regulation of adolescent synaptic pruning. In the present study we used a pharmacological approach to further examine the role of these receptors in altering spine density during puberty of female mice and the impact of these changes on spatial learning, assessed in adulthood. Two drugs were chronically administered during the pubertal period (PND 35-44): the GABA agonist gaboxadol (GBX, 0.1 mg/kg, i.p.), to enhance current gated by alpha 4 beta delta GABARs and the neurosteroid/stress steroid THP (3 alpha-OH-5 beta-pregnan-20-one,10 mg/kg, i.p.) to decrease expression of alpha 4 beta delta. Spine density was determined on PND 56 with Golgi staining. Spatial learning and relearning were assessed using the multiple object relocation task and an active place avoidance task on PND 56. Pubertal GBX decreased spine density post-pubertally by 70% (P < 0.05), while decreasing alpha 4 beta delta expression with THP increased spine density by twofold (P < 0.05), in both cases, with greatest effects on the mushroom spines. Adult relearning ability was compromised in both hippocampus-dependent tasks after pubertal administration of either drug. These findings suggest that an optimal spine density produced by alpha 4 beta delta GABARs is necessary for optimal cognition in adults. (C) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.