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The Pathophysiological Role of Cerebellar Glia in Rett Syndrome

Award Number: R01NS121542
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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The Pathophysiological Role of Cerebellar Glia in Rett Syndrome - PROJECT SUMMARY/ABSTRACT Rett syndrome (RTT) is the leading cause of severe intellectual disability in girls and women. Individuals with RTT develop typically until 6-18 months, when autism-like behaviors and deficits in purposeful hand use and speech start to develop. Loss-of-function mutations in the transcriptional regulator methyl-CpG-binding protein 2 (MECP2) occur in >95% of RTT cases. Initially, researchers regarded MeCP2 deficiency in neurons as the exclusive cause of RTT. However, recent studies have revealed that glia have a pathological role in RTT etiology. Studies have not yet uncovered the underlying cellular mechanisms of glial cell dysfunction in Mecp2 rodent models or the impact of this dysfunction on brain function. In this study, we propose to examine the contribution of a specific glial subtype, Bergmann glia cells (BGs) in the cerebellum, to the motor and social deficits in RTT. We will focus on BGs because (1) cerebellar disruption likely contributes to the motor and social deficits in RTT and (2) BGs are the major glial subtype in the cerebellum. We propose to characterize cerebellar function in conditional knockout (cKO) mice that lack Mecp2 in BGs using a repertoire of approaches, including intracellular whole-cell recordings, in vivo recordings of single units and local field potentials, in vivo and ex vivo imaging of genetically-encoded Ca2+, glutamate, and dopamine (DA) sensors (GCaMP7, iGluSnFr, and dLight1.1, respectively), optogenetics, chemogenetics, near super-resolution confocal microscopy, and behavioral assessments using unbiased machine-learning approaches. Our preliminary results indicate deficits in BGs from Mecp2-deficient mice, including higher expression levels of the GluA1 subunit of AMPA receptors (AMPARs), and depolarized membrane potentials. In addition, we have preliminary evidence of DAergic modulation of BGs through the activation of D1 receptors (D1Rs) activated by either electrical or optogenetic stimulation of DAergic inputs to the cerebellum. Of high relevance to motor and social symptoms in RTT, the expression levels of D1Rs, which modulate GluA1 surface insertion, are higher in Mecp2 KO mice. We hypothesize that BGs in the cerebellum have a pathophysiological role in motor and social deficits in Mecp2-deficient mice. We propose two Aims: (1) Define cerebellar BG dysfunction in Mecp2 cKO mice;; (2) Characterize DAergic modulation of cerebellar BGs in Mecp2 cKO mice. The proposed studies will elucidate the consequences of impaired DAergic modulation of astrocyte function on cerebellar-dependent behaviors, which will have broad implications not only for RTT but also for other brain disorders associated with cerebellar dysfunction.


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: 2026 ( Subtotal = $0 )
2026	2025	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $326,712 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/24/2024	NON-COMPETING CONTINUATION	$328,386
2025	2025	HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	9/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$89,132
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	9/17/2025	NON-COMPETING CONTINUATION	-$90,806
														Subtotal = $326,712

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $364,874 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/7/2023	NON-COMPETING CONTINUATION	$364,874
														Subtotal = $364,874

Issue Date FY: 2022 ( Subtotal = $364,874 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/23/2022	NON-COMPETING CONTINUATION	$36,491
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/14/2022	NON-COMPETING CONTINUATION	$328,383
														Subtotal = $364,874

Issue Date FY: 2021 ( Subtotal = $399,441 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/30/2021	NEW	$399,441
														Subtotal = $399,441

Grand Total All Awards = $1,455,901

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The Pathophysiological Role of Cerebellar Glia in Rett Syndrome

Award Number: R01NS121542

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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