Research ReportRole of α4-containing GABAA receptors in limiting synaptic plasticity and spatial learning of female mice during the pubertal period

- Pubertal impairment of synaptic plasticity is restored by α4 knock-out.
- Pubertal impairment of synaptic plasticity is not restored by α5 blockade.
- Pubertal impairment of spatial learning is restored by α4 knock-out.
- Pubertal α4βδ GABARs impair CNS plasticity and learning.

Expression of α4βδ GABAA receptors (GABARs) increases at the onset of puberty on dendritic spines of CA1 hippocampal pyramidal cells. These receptors reduce activation of NMDA receptors (NMDARs), impair induction of long-term potentiation (LTP) and reduce hippocampal-dependent spatial learning. These effects are not seen in the δ−/− mouse, implicating α4βδ GABARs. Here we show that knock-out of α4 also restores synaptic plasticity and spatial learning in female mice at the onset of puberty (verified by vaginal opening). To this end, field excitatory post-synaptic potentials (fEPSPs) were recorded from the stratum radiatum of CA1 hippocampus in the slice from +/+ and α4−/− pubertal mice (PND 35-44). Induction of LTP, in response to stimulation of the Schaffer collaterals with theta burst stimulation (TBS), was unsuccessful in the +/+ hippocampus, but reinstated by α4 knock-out (~65% potentiation) but not by blockade of α5-GABARs with L-655,708 (50 nM). In order to compare spatial learning in the two groups of mice, animals were trained in an active place avoidance task where the latency to first enter a shock zone is a measure of learning. α4−/− mice had significantly longer latencies by the third learning trial, suggesting better spatial learning, compared to +/+ animals, who did not reach the criterion for learning (120 s latency). These findings suggest that knock-out of the GABAR α4 subunit restores synaptic plasticity and spatial learning at puberty and is consistent with the concept that the dendritic α4βδ GABARs which emerge at puberty selectively impair CNS plasticity.This article is part of a Special Issue entitled SI: Adolescent plasticity.