Hypoactivity and increased variability of neural dynamics in Fragile X circuits

Fragile X syndrome is a neurodevelopmental disorder that has increasingly been associated with circuit-level deficits. To study the development of neural dynamics, while minimizing the effects of compensatory and experiential differences, we examined cortical circuits that developed ex vivo. Whole-cell recordings and two-photon Ca²⁺-imaging of cortical FX slices revealed a developmental delay in the emergence of spontaneous Up-states. This delay was not associated with a decrease in EPSP strength, but there was a subsequent second developmental delay, expressed as a decrease in excitatory drive. At this later time point, the spatiotemporal patterns of activity were significantly more variable in FX circuits.

To determine whether these developmental delays reflect an ontogenetic developmental program, or deficits in neural plasticity—e.g., the ability to homeostatically regulate levels of neural activity—an all-optical approach was used to determine if FX slices underwent normal homeostatic regulation of network activity. To emulate the increase in sensory-driven cortical activity that occurs over early development chronic optical stimulation was over the course of multiple days. Ca²⁺-imaging and whole-cell recordings of FX slices revealed a significant decrease in spontaneous Up-states and EPSP strength, suggesting homeostatic plasticity is intact.

Finally, we examined a new temporal learning paradigm in ex vivo and in vivo cortical circuits. WT circuits learn specific intervals by changing the spatiotemporal pattern to reflect the interval they were trained with. However, FX circuits exhibited abnormal temporal learning. These deficits suggest that FX circuits may not be able to orchestrate multiple forms of synaptic plasticity to generate normal neural dynamics.