MMP-9 gene ablation mitigates hyperhomocystenemia-induced cognition and hearing dysfunction

Area of Science:

• Neuroscience
• Cardiovascular Biology
• Otolaryngology

Background:

• Hyperhomocysteinemia (HHcy) is linked to cognitive decline and hearing loss, potentially via vascular dysfunction.
• Increased matrix metalloproteinase-9 (MMP-9) expression in HHcy is associated with cochlear pathology, but its role in functional deficits is unclear.

Purpose of the Study:

• To investigate the role of MMP-9 in HHcy-induced cognitive and hearing impairments.
• To determine if HHcy-induced MMP-9 activation contributes to vascular, cerebral, and cochlear remodeling, leading to functional deficits.

Main Methods:

• Utilized wildtype (WT), cystathionine-β-synthase heterozygous (CBS(+/-)), MMP-9 knockout (MMP-9(-/-)), and double knockout (CBS(+/-)/MMP-9(-/-)) mice.
• Assessed internal carotid artery (ICA) blood flow using Doppler flowmetry (PSV, PI, RI).
• Evaluated cognitive function with the Novel Object Recognition Test (NORT) and hearing with Auditory Brainstem Response (ABR).

Main Results:

• CBS(+/-) mice exhibited reduced ICA blood flow (decreased PSV, PI, RI), indicating impaired perfusion.
• HHcy mice showed elevated ABR thresholds and reduced ABR amplitude and NORT performance compared to WT and MMP-9(-/-) mice.
• These functional deficits were significantly attenuated in double knockout mice, highlighting MMP-9's crucial role.

Conclusions:

• MMP-9 plays a significant role in HHcy-induced vascular, neural, and cochlear pathophysiology.
• HHcy leads to dual pathology involving reduced blood supply and direct tissue remodeling, mediated by MMP-9.
• This study establishes a direct correlation between MMP-9 and functional deficits in the brain and cochlea.