α4βδ GABAA Receptors Trigger Synaptic Pruning and Reduce Dendritic Length of Female Mouse CA3 Hippocampal Pyramidal Cells at Puberty

Abstract

Synaptic pruning during adolescence is critical for optimal cognition. The CA3 hippocampus contains unique spine types and plays a pivotal role in pattern separation and seizure generation, where sex differences exist, but adolescent pruning has only been studied in the male. Thus, for the present study we assessed pruning of specific spine types in the CA3 hippocampus during adolescence and investigated a possible mechanism in the female mouse. To this end, we used Golgi-impregnated brains from pubertal (~PND 35, assessed by vaginal opening) and postpubertal (PND 56) mice. Spine density was assessed from z-stack (0.1μm steps) images taken using a Nikon DS-U3 camera through a Nikon Eclipse Ci-L microscope and analyzed with NIS Elements. Spine density decreased significantly (P<0.05) during adolescence, with 50-60% decreases in mushroom and stubby spine-types (P<0.05, ~PND35 vs. PND56) in non-proestrous mice. This was associated with decreases in Kalirin-7, a spine protein which stabilizes the cytoskeleton and is required for spine maintenance. Because our previous findings suggest that pubertal increases in α4βδ GABAA receptors (GABARs) trigger pruning in CA1, we investigated their role in CA3. α4 expression in CA3 hippocampus increased 4-fold at puberty (P<0.05), assessed by immunostaining and verified electrophysiologically by an increased response to gaboxadol (100nM), which is selective for α4βδ. Knock-out of α4 prevented the pubertal decrease in Kalirin-7 and synaptic pruning and also increased the dendritic length, demonstrating a

GABA and glutamate in pediatric migraine

“… 43 This implies migraine progression is related to alterations in cortical development. Synaptic pruning is triggered by GABA receptors, which increase in number at pubertal onset 36 . Subsequently, GABA alterations early in development may produce future glutamatergic alterations.…”

Subregional differences in GABAA receptor subunit expression in the rostral ventrolateral medulla of sedentary versus physically active rats

“…Different GABA Aα subunit compositions in sedentary versus active rats could change the affinity of the receptor for GABA and its activation and deactivation rates, thereby altering the properties of the chloride ion channel and leading to GABA A receptors that function differently in sedentary versus active rats. Interestingly, GABA A receptors with a specific subunit composition have recently been shown to affect the extent of dendritic branching and the number of spines on hippocampal neurons (Parato, Shen, & Smith, ), suggesting that the types of GABA A receptors on neurons can influence their morphology. We have previously shown that the dendritic trees of spinally projecting C1 neurons differ between sedentary and active rats and it is tempting to speculate that the GABA A receptor subtypes present on these neurons under sedentary versus physically active conditions could contribute to these dendritic differences.…”

Increased Dendritic Branching of and Reduced δ-GABAA Receptor Expression on Parvalbumin-Positive Interneurons Increase Inhibitory Currents and Reduce Synaptic Plasticity at Puberty in Female Mouse CA1 Hippocampus

“…The decrease in δ expression on, and thus decrease in tonic inhibition of, PV+ interneurons at puberty may be a mechanism for the profuse dendritic branching observed at this time, as dendritic growth is dependent upon NMDA receptor-induced activity (Sepulveda et al, 2010 ). Our previous findings show that in the CA3 hippocampus, knock-out of α4βδ GABARs increases the dendritic branching of CA3 pyramidal cells (Parato et al, 2019 ), suggesting a role for these receptors in limiting dendritic arborization. Other factors that may contribute include the increase in 17β-estradiol (E2) around the time of puberty (Ahima et al, 1997 ), as E2 has been shown to increase dendritic branching of hippocampal neurons (Audesirk et al, 2003 ).…”