Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction

Area of Science:

• Neuroscience
• Cardiovascular Biology
• Developmental Biology

Background:

• A novel GABA signaling pathway exists in embryonic forebrain endothelial cells, independent of neuronal signaling.
• Disruptions in this endothelial GABA_A receptor-GABA signaling pathway early in development are linked to psychiatric disorders.

Purpose of the Study:

• To characterize functional changes in Gabrb3^ECKO mice with selective deletion of the GABA_A receptor β3 subunit in endothelial cells.
• To evaluate the impact of endothelial Gabrb3 loss on cortical blood flow, cardiac tissue, and detailed behavioral alterations.

Main Methods:

• Utilized GABA_A receptor β3 subunit endothelial cell conditional knockout (Gabrb3^ECKO) mice.
• Assessed cortical blood flow, red blood cell velocity, and cardiac histology.
• Conducted behavioral analyses including open field tests, CLAMS testing, and prepulse inhibition assays.

Main Results:

• Gabrb3^ECKO mice exhibited reduced vessel densities and altered morphology in the brain and heart.
• Increased cortical blood flow and velocity were observed, alongside hypertension and cardiac histological changes.
• Significant behavioral deficits were noted, including impaired social interaction, anxiety, depression, memory deficits, and altered startle responses.

Conclusions:

• Vascular GABA_A receptor β3 subunit (Gabrb3) is crucial for both brain and heart function.
• Loss of endothelial Gabrb3 leads to concurrent psychiatric and cardiac dysfunction, highlighting its role in systemic health.