Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model

Abstract

Fmr1 knock-out (ko) mice display key features of fragile X syndrome (FXS), including delayed dendritic spine maturation and FXSassociated behaviors, such as poor socialization, obsessive-compulsive behavior, and hyperactivity. Here we provide conclusive evidence that matrix metalloproteinase-9 (MMP-9) is necessary to the development of FXS-associated defects in Fmr1 ko mice. Genetic disruption of Mmp-9 rescued key aspects of Fmr1 deficiency, including dendritic spine abnormalities, abnormal mGluR5-dependent LTD, as well as aberrant behaviors in open field and social novelty tests. Remarkably, MMP-9 deficiency also corrected non-neural features of Fmr1 deficiency-specifically macroorchidism-indicating that MMP-9 dysregulation contributes to FXS-associated abnormalities outside the CNS. Further, MMP-9 deficiency suppressed elevations of Akt, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E phosphorylation seen in Fmr1 ko mice, which are also associated with other autistic spectrum disorders. These findings establish that MMP-9 is critical to the mechanisms responsible for neural and non-neural aspects of the FXS phenotype.

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

“…At the Drosophila NMJ, we recently showed that both mmp1 and mmp2 mutants strongly alter synaptic architectural development, displaying a mutual suppression mechanism between the secreted and membrane-bound enzymes . Moreover, we have shown previously that pharmacologically or genetically reducing Mmp function corrects the NMJ synaptic architecture defects in the Drosophila FXS disease model (Siller and Broadie, 2011), with similar results reported for the mouse FXS model (Sidhu et al, 2014). Therefore, we hypothesized that Mmp regulation is a major determinant of synaptic architecture.…”

“…4). Motor defects have consistently been found across a range of Mmp manipulations (Brkic et al, 2015;Dansie et al, 2013;Jaworski et al, 2006;Sidhu et al, 2014), although molecular mechanisms had not been identified. Taken together, these results complete our characterization of the entire Drosophila matrix metalloproteome in controlling neuromuscular synapse structure and function .…”

“…In particular, Mmp hyperactivity has been causally implicated in FXS and related ASD conditions (Abdallah and Michel, 2013;Dziembowska et al, 2013;Sidhu et al, 2014;Siller and Broadie, 2011). The synaptic cytoarchitectural phenotypes of timp mutants phenocopy the Drosophila FXS model (Zhang et al, 2001), and trans-synaptic signaling defects are causative in synaptic structural and functional defects in this disease model (Friedman et al, 2013), including BMP signaling (Kashima et al, 2016).…”

Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia: Table 1.

“…[12][13][14] Notably, a well-recognized feature of Fragile X syndrome in humans (ie, elongated dendritic spines that are reproduced in FMRP knockout mice) is accompanied by the excessive production of MMP-9 that, when inhibited, normalizes the spines and alleviates other pathological symptoms, both behavioral and peripheral. 15,16 The well-documented and mechanistically explained role of MMP-9 in driving synaptic plasticity coincides with the function of MMP-9 in phenomena that rely on plasticity, such as learning and memory, addiction, and epileptogenesis, which have been studied in various animal models. 5,7,[17][18][19] MMP-9 apparently plays a special role during developmental plasticity of the postnatal period.…”

Two classes of matrix metalloproteinases reciprocally regulate synaptogenesis

“…Importantly, mammalian Mmps are upregulated in neurological disorders (Huntley, 2012), including multiple sclerosis (Agrawal et al, 2008), epilepsy (Pollock et al, 2014;Wilczynski et al, 2008) and Fragile X syndrome (FXS), the most common heritable determinant of intellectual disability and autism spectrum disorders (Gatto and Broadie, 2011). Similar to the mouse FXS model (Bilousova et al, 2009;Sidhu et al, 2014), the Drosophila FXS disease model exhibits Mmp dysfunction as an underlying cause of neurodevelopmental phenotypes (Siller and Broadie, 2012). Neural defects in the Drosophila FXS model, including impairments in both morphological and functional synaptic differentiation (Doll and Broadie, 2014) are remediated by pharmacological or genetic Mmp inhibition (Siller and Broadie, 2011).…”