Fine-needle aspiration cytology of KIT-negative, PDGFRA-positive epithelioid gastrointestinal stromal tumor of the stomach featuring intranuclear cytoplastic inclusions: Report of a case

Iwa, N.; Yutani, C.; Masuda, K.; Noda, H.; Kobayashi, T.K.

Diagnostic Cytopathology 48(7): 695-697


ISSN/ISBN: 8755-1039
PMID: 32374913
DOI: 10.1002/dc.24465
Accession: 070094076

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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 Trk B 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.