Preventing adolescent synaptic pruning in mouse prelimbic cortex via local knockdown of α4βδ GABA A receptors increases anxiety response in adulthood

Anxiety is increasingly reported, especially in adolescent females. The etiology is largely unknown, which limits effective treatment. Layer 5 prelimbic cortex (L5PL) increases anxiety responses but undergoes adolescent synaptic pruning, raising the question of the impact of pruning on anxiety. Here...

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Bibliographic Details
Published inScientific reports Vol. 11; no. 1; p. 21059
Main Authors Evrard, Matthew R, Li, Michael, Shen, Hui, Smith, Sheryl S
Format Journal Article
LanguageEnglish
Published England 26.10.2021
Subjects
Animals
Anxiety - genetics
Anxiety - metabolism
Brain - metabolism
Female
Gene Knockdown Techniques
Male
Mice
Mice, Knockout
Neuronal Plasticity
Receptors, GABA-A - deficiency
Receptors, GABA-A - metabolism
Sexual Maturation
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Summary:Anxiety is increasingly reported, especially in adolescent females. The etiology is largely unknown, which limits effective treatment. Layer 5 prelimbic cortex (L5PL) increases anxiety responses but undergoes adolescent synaptic pruning, raising the question of the impact of pruning on anxiety. Here we show that preventing L5PL pruning increases anxiety in response to an aversive event in adolescent and adult female mice. Spine density of Golgi-stained neurons decreased ~ 63% from puberty (~ PND35, vaginal opening) to post-puberty (PND56, P < 0.0001). Expression of α4βδ GABA receptors (GABARs) transiently increased tenfold in L5PL at puberty (P < 0.00001), but decreased post-pubertally. Both global and local knockdown of these receptors during puberty prevented pruning, increasing spine density post-pubertally (P < 0.0001), an effect reversed by blocking NMDA receptors (NMDARs). Pubertal expression of the NMDAR-dependent spine protein kalirin7 decreased (50%, P < 0.0001), an effect prevented by α4 knock-out, suggesting that α4βδ-induced reductions in kalirin7 underlie pruning. Increased spine density due to local α4 knockdown at puberty decreased open arm time on the elevated plus maze post-pubertally (62%, P < 0.0001) in response to an aversive stimulus, suggesting that increases in L5PL synapses increase anxiety responses. These findings suggest that prelimbic synaptic pruning is necessary to limit anxiety in adulthood and may suggest novel therapies.
ISSN:2045-2322