Hypoplasticity in sensory-driven necortical circuits of Fragile X mice

Abstract

Sensory experience and perceptual learning modify the receptive field properties of cortical pyramidal neurons (PNs), primarily through long-term potentiation (LTP). Repetitive sensory stimulation or rhythmic whisker stimulation (RWS), at behaviourally relevant frequencies (8 Hz), can induce long-term potentiation (LTP) of excitatory synapses in typically developing mice in the somatosensory cortex (S1). Fragile X syndrome (FXS) is a leading single gene inherited form of intellectual disability and altered somatosensory processing is a prevalent feature. The Fragile X mouse model (Fmr1-/y mice) similarly exhibits altered somatosensory processing, including altered neuronal circuit function in S1. To assess if LTP in Layer (L) 2/3 PNs is intact upon changes in S1 circuit function we performed ex vivo whole-cell electrophysiology and in vivo two-photon calcium imaging of layer (L) 2/3 pyramidal neurons (PNs) in the S1 cortex of adult male Fragile X (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 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, which may be consistent with findings of shortened axon initial segment (AIS) length. We also observed an increase in adaptation to repetitive stimulation in Fmr1-/y L2/3 PNs compared to controls, which may underlie failure to induce plasticity. These findings suggest that L2/3 PNs of S1 in Fmr1-/y mice are hypoplastic, potentially related to disrupted inhibitory control and rapid adaptation during repetitive sensory stimulation. Altogether, impaired LTP in the sensory cortex suggests that the receptive field properties of cortical PNs are less flexible and dynamic, which may contribute to altered somatosensory processing and reactivity in FXS.