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

Award Number: R01HD092369
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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 disorders, such as mood, cognitive disorders and metabolic disorders such as obesity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	5	11/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $398,748 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	001	5	6/15/2022	NON-COMPETING CONTINUATION	$398,748
2022	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	4	6/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $398,748

Issue Date FY: 2021 ( Subtotal = $398,748 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	4	6/22/2021	NON-COMPETING CONTINUATION	$398,748
														Subtotal = $398,748

Issue Date FY: 2020 ( Subtotal = $406,885 )
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	3	6/18/2020	NON-COMPETING CONTINUATION	$406,885
														Subtotal = $406,885

Issue Date FY: 2019 ( Subtotal = $406,885 )
2019	2019	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	001	2	5/23/2019	NON-COMPETING CONTINUATION	$406,885
2019	2018	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	1	11/15/2018	NEW	$0
														Subtotal = $406,885

Issue Date FY: 2018 ( Subtotal = $420,135 )
2018	2018	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Child Health and Human Development Extramural Research	000	1	9/1/2018	NEW	$420,135
														Subtotal = $420,135

Grand Total All Awards = $2,031,401

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

Award Number: R01HD092369

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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