Acute pharmacological inhibition of matrix metalloproteinase-9 activity during development restores perineuronal net formation and normalizes auditory processing in Fmr1 KO mice

被引:44
作者
Pirbhoy, Patricia S. [1 ]
Rais, Maham [1 ]
Lovelace, Jonathan W. [2 ]
Woodard, Walker [1 ]
Razak, Khaleel A. [2 ]
Binder, Devin K. [1 ]
Ethell, Iryna M. [1 ]
机构
[1] Univ Calif Riverside, Div Biomed Sci, Sch Med, Riverside, CA 92521 USA
[2] Univ Calif Riverside, Dept Psychol, Riverside, CA 92521 USA
关键词
electroencephalography; fragile X syndrome; matrix metalloproteinase-9; parvalbumin; perineuronal nets; sensory hypersensitivity; FRAGILE-X-SYNDROME; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MOUSE MODEL; GENETIC REMOVAL; MINOCYCLINE TREATMENT; NEUROTROPHIC FACTOR; GAMMA OSCILLATIONS; VISUAL RESPONSES; NEURONS; AUTISM;
D O I
10.1111/jnc.15037
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Individuals with Fragile X Syndrome (FXS) and autism spectrum disorder (ASD) exhibit cognitive impairments, social deficits, increased anxiety, and sensory hyperexcitability. Previously, we showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to abnormal development of parvalbumin (PV) interneurons and perineuronal nets (PNNs) in the developing auditory cortex (AC) of Fmr1 knock-out (KO) mice, which likely underlie auditory hypersensitivity. Thus, MMP-9 may serve as a potential target for treatment of auditory hypersensitivity in FXS. Here, we used the MMP-2/9 inhibitor, SB-3CT, to pharmacologically inhibit MMP-9 activity during a specific developmental period and to test whether inhibition of MMP-9 activity reverses neural oscillation deficits and behavioral impairments by enhancing PNN formation around PV cells in Fmr1 KO mice. Electroencephalography (EEG) was used to measure resting state and sound-evoked electrocortical activity in auditory and frontal cortices of postnatal day (P)22-23 male mice before and one-day after treatment with SB-3CT (25 mg/kg) or vehicle. At P27-28, animal behaviors were tested to measure the effects of the treatment on anxiety and hyperactivity. Results show that acute inhibition of MMP-9 activity improved evoked synchronization to auditory stimuli and ameliorated mouse behavioral deficits. MMP-9 inhibition enhanced PNN formation, increased PV levels and TrkB phosphorylation yet reduced Akt phosphorylation in the AC of Fmr1 KO mice. Our results show that MMP-9 inhibition during early postnatal development is beneficial in reducing some auditory processing deficits in the FXS mouse model and may serve as a candidate therapeutic for reversing sensory hypersensitivity in FXS and possibly other ASDs.
引用
收藏
页码:538 / 558
页数:21
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