Synaptic pruning in the female hippocampus is triggered at puberty by extrasynaptic GABAA receptors on dendritic spines

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Abstract

Adolescent synaptic pruning is thought to enable optimal cognition because it is disrupted in certain neuropathologies, yet the initiator of this process is unknown. One factor not yet considered is the α4βδ GABA_A receptor (GABAR), an extrasynaptic inhibitory receptor which first emerges on dendritic spines at puberty in female mice. Here we show that α4βδ GABARs trigger adolescent pruning. Spine density of CA1 hippocampal pyramidal cells decreased by half post-pubertally in female wild-type but not α4 KO mice. This effect was associated with decreased expression of kalirin-7 (Kal7), a spine protein which controls actin cytoskeleton remodeling. Kal7 decreased at puberty as a result of reduced NMDAR activation due to α4βδ-mediated inhibition. In the absence of this inhibition, Kal7 expression was unchanged at puberty. In the unpruned condition, spatial re-learning was impaired. These data suggest that pubertal pruning requires α4βδ GABARs. In their absence, pruning is prevented and cognition is not optimal.

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Sonia Afroz

Department of Biomedical Sciences, University of California, Riverside, Riverside, United States

Competing interests
The authors declare that no competing interests exist.
Julie Parato

Department of Physiology and Pharmacology, SUNY Downstate Medical Center, Brooklyn, United States

Competing interests
The authors declare that no competing interests exist.
Hui Shen

School of Biomedical Engineering, Tianjin Medical University, Tianjin, China

Competing interests
The authors declare that no competing interests exist.
Sheryl Sue Smith

Department of Physiology and Pharmacology, SUNY Downstate Medical Center, Brooklyn, United States

For correspondence
sheryl.smith@downstate.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#13-10374) of SUNY Downstate Medical Center (Animal Welfare Assurance Number: A3260-01). All perfusions were performed under urethane anesthesia, and every effort was made to minimize suffering.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.