Hypoplasticity in sensory-driven neocortical circuits of the Fragile X syndrome mouse model

Sensory experience and learning are tightly linked to plasticity in neocortical circuits. Repetitive sensory stimulation—such as rhythmic whisker stimulation (RWS) at behaviourally relevant frequencies (∼8 Hz)—can induce long-term potentiation (LTP) of excitatory synapses in typically developing mice. Fragile X syndrome (FXS), a leading monogenically inherited form of intellectual disability, is associated with altered tactile reactivity, where non-noxious touch can be aversive.

To investigate how sensory-evoked plasticity is altered in FXS, we combined ex vivo whole-cell electrophysiology with in vivo two-photon calcium imaging of layer (L) 2/3 pyramidal neurons (PNs) in the Somatosensory (S1) cortex of adult male Fragile X mouse model ( Fmr1 ^-/y ) mice and typically developing ( Fmr1 ^+/y ) control littermates. We found that plasticity induced by repetitive sensory stimulation was impaired in Fmr1 ^-/y mice ex and in vivo compared to controls. L4-evoked subthreshold synaptic responses were hyperexcitable in L2/3 PNs, consistent with circuit-level disinhibition. Despite this, baseline intrinsic spiking evoked by current steps remained largely unchanged and whisker-evoked activity appeared diminished in vivo . We observed a shortening of the axon initial segment (AIS) in L2/3 in Fmr1 ^-/y compared to control mice, which may reveal a potential mechanism to explain why subthreshold hyperexcitability did not induce more spiking. We also observed an increase in adaptation to the repetitive stimulation in Fmr1 ^-/y mice compared to controls, which may underlie failure to induce plasticity. Together, these findings suggest that L2/3 PNs of S1 in Fmr1 ^-/y mice are locked in a hypoplastic state, potentially related to disrupted inhibitory control, AIS shortening, and rapid adaptation during repetitive sensory stimulation. As somatosensory processes underly tactile perception, these findings may potentially underly altered tactile reactivity in FXS.