FUNCTIONAL ALTERATIONS OF PARVALBUMIN INTERNEURONS CONTRIBUTING TO ABNORMAL NETWORK ACTIVITY IN ALZHEIMER'S…

Assistance award details

Assistance award identifier

ASST_NON_R00AG062776_075

FAIN

R00AG062776

Recipient

UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$742,002

Period

Apr 15, 2023 – Jan 31, 2026

Fiscal year

2023

Place of performance state

TX

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

FUNCTIONAL ALTERATIONS OF PARVALBUMIN INTERNEURONS CONTRIBUTING TO ABNORMAL NETWORK ACTIVITY IN ALZHEIMER'S DISEASE MOUSE MODELS - PROJECT SUMMARY/ABSTRACT ALZHEIMER'S DISEASE (AD) IS THE MOST COMMON FORM OF DEMENTIA AND THE SIXTH LEADING CAUSE OF DEATH IN THE U.S. THAT AFFECTS 5.7 MILLION AMERICANS. THERE IS NO CURE FOR AD AND IT HAS BEEN 15 YEARS SINCE THE LATEST AD DRUG, MEMANTINE, WAS APPROVED BY THE FDA. REMARKABLY, AD PATIENTS SHOW FLUCTUATIONS OF COGNITIVE FUNCTION IN THE COURSE OF HOURS OR DAYS. THIS BEHAVIOR CANNOT BE EXPLAINED BY THE SUDDEN LOSS OR GAIN OF NEURONS, NEUROFIBRILLARY TANGLES OR BETA-AMYLOID PLAQUES. INSTEAD, LUCID MOMENTS EXPERIENCED BY AD PATIENTS LIKELY REPRESENT EMERGENCE OF NORMAL NEURONAL NETWORK ACTIVITY THAT IS DISRUPTED BY PATHOLOGICAL EVENTS IN THE AD BRAIN. IN BOTH AD PATIENTS AND MOUSE MODELS OF AD, NEURONAL NETWORK HYPERSYNCHRONY (EPILEPTIFORM DISCHARGES AND SEIZURES) AND ALTERED OSCILLATORY NETWORK ACTIVITY (BRAIN RHYTHMS) ARE OBSERVED. RECENT DISCOVERIES SHOW THAT INHIBITORY INTERNEURON DYSFUNCTION IS A KEY UPSTREAM MECHANISM LEADING TO NETWORK HYPERSYNCHRONY, DECREASED BEHAVIOR-DEPENDENT GAMMA OSCILLATORY POWER AND IMPAIRED COGNITIVE FUNCTION IN THE J20 MODEL OF AD. DEFICITS IN INHIBITORY INTERNEURONS ARE FOUND IN BOTH AD PATIENTS AND MOUSE MODELS OF AD WHERE LEVELS OF THE VOLTAGE-GATED SODIUM CHANNEL SUBUNIT NAV1.1 ARE DECREASED IN THE PARIETAL CORTEX. NAV1.1 IS PREDOMINANTLY EXPRESSED IN THE PARVALBUMIN (PV)-POSITIVE INHIBITORY INTERNEURONS, WHICH GENERATE GAMMA OSCILLATORY ACTIVITY THAT INCREASES DURING SENSORIMOTOR AND COGNITIVE. PV INTERNEURONS ARE CRITICAL IN MODULATING COGNITION-ASSOCIATED GAMMA OSCILLATORY ACTIVITY, HOWEVER, THE IN VIVO FUNCTIONAL DEFICITS OF PV INTERNEURONS AND HOW PV INTERNEURONS CONTRIBUTE TO DISRUPTED GAMMA RHYTHMS AND NETWORK HYPERSYNCHRONY IN AD IS UNKNOWN. USING IN VIVO TWO-PHOTON IMAGING, ELECTROENCEPHALOGRAM (EEG) RECORDINGS AND BEHAVIORAL ASSESSMENTS, THE RELATIONSHIP BETWEEN IN VIVO PV CELL A