Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome

Abstract

Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase −9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS.

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

“…This pattern of alterations may contribute to previously reported decreases in transient gamma phase-locking [13]. Given the similar network dynamics observed in Fmr1 rodent models [5, 7, 14, 44], findings reported here may not only extend mouse model concepts to FXS patients, but suggest that neurophysiological measures may be useful for tracking this local circuit deficit in both mouse models and patients to foster direct translational drug development for this neurodevelopmental disorder.…”

“…Related findings have been reported in Fmr1 KO mice [14]. Our findings linking gamma power and sensory hypersensitivities in FXS patients suggest a convergence with FXS animal model findings of altered local inhibitory networks in and highlight the need for more systematic study of gamma-band neural activity in FXS.…”

Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

“…Most encouragingly, Fmr1 KO mice also exhibit sensory system deficits. These deficits have been measured in terms of increased susceptibility to audiogenic seizures, increased response of sensory cortex to stimuli (Rotschafer and Razak, 2014; Zhang et al, 2014), increased UP states in sensory cortex (Hays et al, 2011), increased spontaneous and correlated activity in sensory cortex (Goncalves et al, 2013) and reduced habituation of sensory stimulus evoked responses (Lovelace et al, 2016). Some of these deficits may arise due to abnormal critical period plasticity during development (Contractor et al, 2015; Kim et al, 2013).…”

“…Preliminary data based on auditory ERPs from the Fmr1 KO mouse cortex suggests a more directly translation relevant phenotype in the mouse (Lovelace et al, 2016). Auditory ERPs were measured using electrodes placed between 200 and 400 μm deep in the primary auditory cortex of anesthetized Fmr1 KO and WT mice.…”

“…Experimental approaches which measure sensory processing are emerging as powerful translational tools in this regard. Studies using EEG, magnetoencephalography (MEG) or startle/EMG point to analogous sensory processing deficits in humans and animal models (Castrén et al, 2003; Connolly et al, 2004; Ehrlichman et al, 2008; Ethridge et al, 2016; Harms et al, 2014; Lovelace et al, 2016; Maxwell et al, 2004; Nakamura et al, 2011; Siegel et al, 2003; Umbricht et al, 2004) and have facilitated examination of underlying mechanisms of sensory disorders in rodent models relevant to ASD/FXS. Furthermore, such studies take advantage of the properties of the neural circuitry underlying basic sensory processing, which is better characterized and may be more conserved across species than neural circuitry underlying complex social and communication behaviors.…”