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

Abstract

BackgroundSensory 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).MethodsWe 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.ResultsReceptive 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.ConclusionsFmr1 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.

Reduced axonal caliber and structural changes in a rat model of Fragile X syndrome with a deletion of a K-Homology domain of Fmr1

“…However, other regions and white matter tracts that are also implicated in attention show anatomical alterations in FXS, such as the thalamus, internal capsule, and the splenium of the corpus callosum 4 . Structural deficits in white matter have also been identified in Fmr1 knockout (KO) mice and resemble those seen in individuals with FXS [5][6][7] . Importantly, this includes regions known to be recruited during visuospatial attention, namely, the superior colliculus, the splenium of the corpus callosum, and the white matter of the medial prefrontal cortex.…”

A Chrnb3‐Cre BAC transgenic mouse line for manipulation of gene expression in retinal ganglion cells

“…Adult mice were anesthetized with a Ketamine/Xylazine (100/10 mg/kg). Approximately 500 nL of CTB‐488 (2 mg/mL in PBS) was injected using a pulled‐glass micropipette using a Picospritzer III (Parker‐Hannifin), as described previously (Kay, Gabreski, & Triplett, ). Animals were euthanized 2 days post‐injection, as described above, and brains were dissected and post‐fixed in 4% PFA overnight.…”

Reduced axonal caliber and white matter changes in a rat model of Fragile X syndrome with a deletion of a K Homology domain of Fmr1

“…Each experimental animal was scanned in the MRI the same day as a same-sex control animal. Images with obvious artifacts or masks 6 that did not align to the image were excluded before the statistical analyses commenced.…”

“…However, other regions and white matter tracts that are also implicated in attention show anatomical alterations in FXS, such as the thalamus, internal capsule, and the splenium of the corpus callosum [4]. Structural deficits in white matter have also been identified in Fmr1 knockout (KO) mice and resemble those seen in individuals with FXS [5][6][7]. Importantly, this includes regions known to be recruited during visuospatial attention, including the superior colliculus, and the tracts that connect them, including the splenium of the corpus callosum and the white matter of the medial prefrontal cortex.…”

“…Importantly, we discovered volumetric changes and alterations in diffusion in both gray and white matter regions that are also impaired in Fmr1 KO mice and individuals with FXS.Using a semi-automated region-based analysis of T2 images, we determined that the superior colliculus increased in absolute volume in Fmr1-Δ exon 8 -/y rats and validated this in a fully automated analysis. The superior colliculus is also impaired in Fmr1 KO mice[6] and implicated in the orienting component of attention. Second, the genu of the corpus callosum increased in both absolute and relative volume in Fmr1-Δ exon 8 -/+ rats compared to WT littermates.…”