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Homeostatic Inhibitory Control of Cortical Hyperexcitability in Fragile X Syndrome

In mouse models of Fragile X Syndrome (FXS), cellular and circuit hyperexcitability are a consequence of altered brain development [reviewed in (Contractor et al., 2015)]. Mechanisms that favor or hinder plasticity of synapses could affect neuronal excitability. This includes inhibitory long term depression (I-LTD) – a heterosynaptic form of plasticity that requires the activation of metabotropic glutamate receptors (mGluRs). Differential circuit maturation leads to shifted time points for critical periods of synaptic plasticity across multiple brain regions (Harlow et al., 2010; He et al., 2014), and disruptions of the development of excitatory and inhibitory synaptic function are also observed both during development and into adulthood (Vislay et al., 2013). However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Our results demonstrate that the somatosensory cortex of the Fmr1 KO mouse model of FXS exhibits increased GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired plasticity processes. We find the overall diminished mGluR activation in the Fmr1 KO mice leads to both a decreased spontaneous inhibitory postsynaptic input to principal cells and also to a disrupted form of inhibitory long term depression (I-LTD). In cortical synapses, this I-LTD is dependent on mGluR activation and the mobilization endocannabinoids (eCBs). Notably, these data suggest enhanced hyperexcitable phenotypes in FXS may be homeostatically counterbalanced by the inhibitory drive of the network and its altered response to mGluR modulation. Significance Statement Fragile X Syndrome is a pervasive neurodevelopmental disorder characterized by intellectual disability, autism, epilepsy, anxiety and altered sensory sensitivity. In both in vitro and in vivo recordings in the somatosensory cortex of the Fmr1 knockout mouse model of Fragile X Syndrome we show that hyperexcitable network activity contributes to ineffective synaptic plasticity at inhibitory synapses. This increased excitability prevents cortical circuits from adapting to sensory information via ineffective plasticity mechanisms.