# Leptin regulation of GABAergic synaptogenesis and excitation-inhibition balance during development: effects of maternal obesity

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $406,885

## Abstract

Leptin is a critical neurotrophic factor during development. Its receptors (LepRs) are found throughout the
brain, including in the hippocampus. Leptin deficiency is also associated with cognitive and emotional
impairment, behaviors impacted by hippocampal function. Intriguingly, leptin levels rise during a critical
developmental period when hippocampal synaptogenesis is occurring. We have demonstrated that leptin
induces GABAergic synaptogenesis and controls Cl- homeostasis to promote an excitatory effect of GABA
during this critical period. In contrast, a lack of leptin shifts the excitation/inhibition balance so that GABA is
more inhibitory, and reduces GABAergic synaptogenesis. Excessive leptin during development
(hyperleptinemia) prolongs the excitatory action of GABA and increases GABA receptor expression,
suggesting that it may have long-term effects on hippocampal function. Intriguingly, leptin levels are
elevated in children with early onset autism spectrum disorders (ASD) and Rett syndrome, a disease
showing “autistic-like” behaviors. Maternal obesity, which affects 1 in 5 pregnancies, is also associated with
hyperleptinemia in humans, and also heightens the risk of ASD and other neuropsychiatric disorders in
children. One potential mechanism by which maternal obesity, and the associated hyperleptinemia, could
impact the likelihood of a child or an adult developing emotional and cognitive disorders is through
alterations in the development, maintenance, function or plasticity of GABAergic connections. However, the
effects of hyperleptinemia and maternal obesity on the development and function of GABA synapses is not
known. Understanding how maternal obesity alters the developmental effects of leptin and the formation of
critical hippocampal synaptic connections in vivo is an essential first step to understanding the mechanisms
by which maternal obesity impacts hippocampal function later in life. Our central hypothesis is that leptin
plays a key role in regulating GABAergic synaptic development and plasticity and that pathological
hyperleptinemia alters this process through changes in the expression and membrane localization of key
components of GABAergic synapses and regulators of Cl- homeostasis. We will test our central hypothesis
with three specific aims. 1) Determine how leptin alters Cl- homeostasis and stimulates GABAergic
synaptogenesis in vivo 2) Determine whether developmental leptin impacts GABAergic synaptic function
and plasticity. 3) Determine if maternal obesity and associated hyperleptinemia alters GABAergic
synaptogenesis, Cl- homeostasis and GABAergic synaptic function and plasticity. While we have focused
on the hippocampus, this knowledge is expected to have broad impact, as it should also be applicable to
leptin-induced synapse formation in other brain regions, including pathways critical for the control of food
intake and energy homeostasis. This research therefore should have implications for both mental health
dis...

## Key facts

- **NIH application ID:** 9934259
- **Project number:** 5R01HD092369-03
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Gary Allen Wayman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,885
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934259

## Citation

> US National Institutes of Health, RePORTER application 9934259, Leptin regulation of GABAergic synaptogenesis and excitation-inhibition balance during development: effects of maternal obesity (5R01HD092369-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934259. Licensed CC0.

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