# Effect of GABAergic inhibition of dendritic spines on synaptic pruning in the medial prefrontal cortex during adolescence

> **NIH NIH R01** · SUNY DOWNSTATE MEDICAL CENTER · 2021 · $629,227

## Abstract

Dendritic spines undergo synaptic pruning in the medial prefrontal cortex (mPFC) during adolescence,
a process which is excessive in schizophrenia, believed to underlie cognitive impairment. Despite its
importance, the mechanism underlying synaptic pruning in the mPFC is not known. Our preliminary
findings suggest that extrasynaptic α4βδ GABAA receptors (GABARs), which transiently emerge on the
spine at puberty onset (~PND 35) for 10d, trigger adolescent synaptic pruning in the mPFC. These
receptors generate a shunting inhibition which impairs NMDA receptor activation. Our previous findings
in CA1 hippocampus established that the inhibition generated by these receptors reduces expression of
the Rho-GEF spine protein Kalirin-7, necessary for spine maintenance, via this reduced NMDA receptor
activity. We will test the hypothesis that similar effects on spine proteins play a role in adolescent
pruning in mPFC. The proposed aims will use multiple techniques, including in vivo two-photon
imaging, electrophysiological, pharmacological, and immunocytochemical assays. To this end, we will
chronically manipulate α4βδ function during adolescence (~PND 35-44) and quantify spine density at 8
and 12 wks of age. Preliminary data shows that spine density is decreased in both layer 3 and 5 post-
pubertally in +/+ but not α4-/- mice, implicating α4βδ GABARs. Because synaptic GABAergic input
targets the spine in the cortex, the role of α1β2γ2 GABARs will also be examined. These experiments
will use acute pharmacological (agonists, modulators) and genetic manipulation (global/conditional/local
knock-down) of α4βδ and α1β2γ2 to explore the role of these receptors in regulating spine density and
morphology assessed using Golgi and electrophysiological techniques. To explore the effect of this
pruning on circuit and behavioral plasticity, in vivo two-photon techniques in combination with multi-
neuron recording will be used to image the Ca++ signals and record activity generated by neuronal
ensembles in response to visual stimuli in the awake mouse across adolescence and after GABAR
modulation/knock-down. We will thus assess the effect of pubertal α4βδ GABARs and GABAR-
generated pruning on circuit function, including the power and synchronization of theta and gamma
oscillations as well as on circuit activity/synchronization of ensembles and mPFC-dependent learning
tasks. The findings from the proposed studies will directly address the functional role of GABAergic
inhibition on dendritic spines at puberty, and will also provide mechanisms for the process of synaptic
pruning, as well as explore functional outcomes of alterations in this process. These results are relevant
for schizophrenia where excessive synaptic pruning and impaired working memory are reported in
association reduced power/sychronization of visually-evoked gamma oscillations, and where single
nucleotide polymorphisms of the δ gene are reported, suggesting a genetic link.

## Key facts

- **NIH application ID:** 10054963
- **Project number:** 5R01MH115900-03
- **Recipient organization:** SUNY DOWNSTATE MEDICAL CENTER
- **Principal Investigator:** Sheryl S Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $629,227
- **Award type:** 5
- **Project period:** 2018-12-06 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054963

## Citation

> US National Institutes of Health, RePORTER application 10054963, Effect of GABAergic inhibition of dendritic spines on synaptic pruning in the medial prefrontal cortex during adolescence (5R01MH115900-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10054963. Licensed CC0.

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