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Astrocyte Connexin 43 Phosphorylation in Seizure Susceptibility after Traumatic Brain Injury

Award Number: F31NS145625
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/13/2027
PERIOD OF PERFORMANCE END DATE: 02/12/2028

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Astrocyte Connexin 43 Phosphorylation in Seizure Susceptibility after Traumatic Brain Injury - PROJECT SUMMARY Traumatic brain injury (TBI) aﬀects roughly 69 million people annually and about 2.56 million subsequently develop post-traumatic epilepsy (PTE), yet no therapy prevents PTE, highlighting the need to identify early, targetable mechanisms that drive epileptogenesis. Astrocytes maintain extracellular ion balance and supply metabolic support and, through brain-wide coupling via Connexin-43 (Cx43) gap junctions, are positioned to shape circuit excitability after injury. Despite extensive study, the role of astrocyte coupling in PTE remains controversial. Some work claims coupling restrains seizures by buﬀering extracellular potassium, whereas other studies claim coupling spreads pro-convulsive metabolites. However, these prior works did not assess coupling’s eﬀects on neuronal activity in models that reproduce TBI-speciﬁc pathology. At the molecular level, Cx43 function is mediated by phosphorylation, and after TBI our laboratory observes increased phosphorylation at serine-368 (pS368), a modiﬁcation that in heart and kidney closes Cx43 channels and precedes their internalization and degradation. Consistent with a pathological role for this modiﬁcation, preliminary data reveals mice harboring a non-phosphorylatable S368A substitution are protected from TBI- induced seizure susceptibility even though they display fewer Cx43 plaques, a structural readout that does not report whether channels are open or closed; thus, it remains unknown whether protection reﬂects preserved functional coupling, altered Cx43 turnover, or both. This proposal tests the hypothesis that TBI promotes seizure susceptibility through pS368-mediated astrocyte uncoupling. Aim 1 will test how selective closure of astrocytic Cx43 gap junctions shapes seizure susceptibility and PTE. I will express a Tet-On–inducible, dominant-negative Cx43T154A via astrocyte-tropic AAV-PHP.eB to close Cx43 gap junctions in adult C57BL/6 mice. Seizure susceptibility will be quantiﬁed with a repeated subconvulsive pentylenetetrazol paradigm and behavioral Racine scoring, and PTE incidence, latency, and burden will be measured by long-term electroencephalography after diﬀuse weight-drop TBI. Aim 2 will deﬁne how TBI-induced Cx43 pS368 regulates astrocyte coupling and Cx43 turnover by combining S368A knock-in mice with dye-ﬁlling assays of functional coupling and biochemical and imaging-based measures of Cx43 internalization and degradation. Together, these studies will establish whether S368 phosphorylation–mediated astrocyte uncoupling drives post-traumatic hyperexcitability and PTE and will evaluate Cx43 pS368 and astrocyte network coupling as mechanistic targets for preventing post-traumatic epilepsy.


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 = $41,809 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/13/2026	NEW	$41,809
														Subtotal = $41,809

Grand Total All Awards = $41,809

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Astrocyte Connexin 43 Phosphorylation in Seizure Susceptibility after Traumatic Brain Injury

Award Number: F31NS145625

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/13/2027

PERIOD OF PERFORMANCE END DATE: 02/12/2028

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