Visual subcircuit-specific dysfunction and input-specific mispatterning in the superior colliculus of fragile X mice

BACKGROUND: Sensory processing deficits are frequently co-morbid with neurodevelopmental disorders. For example, patients with fragile X syndrome (FXS), caused by a silencing of the FMR1 gene, exhibit impairments in visual function specific to the dorsal system, which processes motion information. However, the developmental and circuit mechanisms underlying this deficit remain unclear. Recently, the superior colliculus (SC), a midbrain structure regulating head and eye movements, has emerged as a model for dissecting visual circuit development and function. Previous studies have demonstrated a critical role for activity-dependent processes in the development of visual circuitry in the SC. Based on the known role of the FMR1 gene product in activity-dependent synaptic plasticity, we explored the function and organization of visual circuits in the SC of a mouse model of FXS (Fmr1(−/y)). METHODS: We utilized in vivo extracellular electrophysiology in combination with computer-controlled visual stimuli to determine the receptive field properties of visual neurons in the SC of control and Fmr1(−/y) mice. In addition, we utilized anatomical tracing methods to assess the organization of visual inputs to the SC and along the retinogeniculocortical pathway. RESULTS: Receptive fields of visual neurons in the SC of Fmr1(−/y) mice were significantly larger than those found in control animals, though their shape and structure were unaffected. Further, selectivity for direction of movement was decreased, while selectivity to axis of movement was unchanged. Interestingly, axis-selective (AS) neurons exhibited a specific hyperexcitability in comparison to AS neurons in control SC and to direction-selective (DS) neurons in both control and Fmr1(−/y) SC. Anatomical tracings revealed that retinocollicular, retinogeniculate, and geniculocortical projections were normally organized in the absence of Fmr1. However, projections from primary visual cortex (V1) to the SC were poorly refined. CONCLUSIONS: Fmr1 is required for the proper development of visual circuit organization and function in the SC. We find that visual dysfunction is heterogeneously manifested in a subcircuit-specific manner in Fmr1(−/y) mice, consistent with previous studies in human FXS patients. Further, we show a specific alteration of inputs to the SC from V1, but not the retina. Together, these data suggest that Fmr1 may function in distinct ways during the development of different visual subcircuits.