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

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 GABAA 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.DOI: http://dx.doi.org/10.7554/eLife.15106.001

α4βδ 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

“…Thus, there has been recent interest in the mechanisms that underlie synaptic pruning which can involve microglia (Paolicelli et al, 2011) and autophagy (Tang et al, 2014), likely the final steps in the pruning process. Our recent findings (Afroz et al, 2016) suggest that adolescent synaptic pruning in the CA1 hippocampus of the female mouse is triggered by the tonic inhibition generated by α4βδ GABA A receptors (GABARs). These receptors emerge on the dendritic spine at the onset of puberty (Shen et al, 2010), identified by vaginal opening (typically ~PND 35), and remain at high levels for the next 10 days (Aoki et al, 2012).…”

“…At puberty, α4βδ GABARs impair the activation of NMDA receptors (NMDARs) (Shen et al, 2010, Afroz et al, 2016) which are necessary for spine maintenance (Ultanir et al, 2007) via their regulation of spine proteins which stabilize the actin cytoskeleton (Afroz et al, 2016). This process produces the dramatic decrease in spine density during the pubertal period, based on results comparing wild-type with the α4−/− mouse (Afroz et al, 2016) which is also a functional δ knock-out (Sabaliauskas et al, 2012, Peng et al, 2014).…”

“…This process produces the dramatic decrease in spine density during the pubertal period, based on results comparing wild-type with the α4−/− mouse (Afroz et al, 2016) which is also a functional δ knock-out (Sabaliauskas et al, 2012, Peng et al, 2014). …”

“…Thus, spine density changes may produce a greater impact in the female hippocampus than in the male. In addition, the role of tonic inhibition in spatial learning and plasticity has been well-characterized at puberty in the female rodent (Shen et al, 2010, Aoki et al, 2012, Afroz et al, 2016) and has been shown to play a pivotal role in synaptic pruning in the female CA1 hippocampus (Afroz et al, 2016). …”

“…When pruning is prevented, as observed in the α4−/− mouse, spatial learning is normal, but re-learning a new location is impaired (Afroz et al, 2016). Therefore, in the present study we also compared the effect of pubertal GBX and THP administration on spatial learning and relearning ability in adulthood using the multiple placement object relocation task (MPORT) and an active place avoidance task (APA), assessed post-pubertally.…”