title: Impact of sensory cortex dysfunction on sensory perception
Creators: name: Bendova, Sarah
Publisher: name: The University of Edinburgh
Year: 2025
Subjects: subject: sensory cortex dysfunction
subject: sensory perception
subject: Tactile sensitivities
subject: autism
subject: Fragile X Syndrome
subject: Messenger Ribonucleoprotein
subject: barrel cortex
subject: rhythmic paired stimulation
subject: long-term potentiation
subject: rhythmic whisker stimulation
subject: AMPA receptor
subject: postsynaptic density protein-95 (PSD95)

description: Tactile sensitivities are a core feature of autism, which often manifest in early childhood as aversions to non-harmful touch, such as food or clothing textures. These sensitivities are reported in up to 70% of individuals with autism and are thought to perpetuate aversions, anxiety and maladaptive behaviours including self-harm. Current therapies for autism are limited and fail to address sensory impairments, making the understanding of sensory function imperative for discovery of new treatments targets. Fragile X Syndrome (FXS) is the leading monogenic cause of intellectual disability, with 30-60% of individuals also diagnosed with autism. FXS is caused by the transcriptional silencing of the FMR1 gene, leading to a deficiency in Fragile X Messenger Ribonucleoprotein (FMRP), which has crucial roles at both synaptic and circuit levels. It is becoming increasingly apparent that synaptic plasticity, which is the change in the synaptic strength and thus the connections between neurons, underpins sensory experience and perceptual learning. The mouse whisker system serves as a powerful tool for studying sensory processing as whiskers are a major processing hub of tactile information in rodents. Tactile information is encoded in the primary somatosensory cortex (S1), with whisker input being somatotopically represented across the barrel cortex (BC). In typically developing mice, rhythmic paired stimulation (RPS) of lower- and higher-order thalamocortical projections, carrying respectively sensory and contextual information, triggers a form of synaptic plasticity termed long-term potentiation (LTP) in cortical layer 2/3 (L2/3) pyramidal neurons (PNs) in S1 ex vivo. This LTP is suggested to share mechanisms with potentiation driven by rhythmic whisker stimulation (RWS), which is a passive repetitive whisker stimulation paradigm, in vivo. Preliminary data indicate that L2/3 LTP is impaired ex vivo in Fmr1-KO mice, a genetic rodent model of FXS that also exhibits tactile impairments. I therefore hypothesised that RWSevoked plasticity will also be impaired in vivo at L2/3 of S1 in Fmr1-KO mice. To test this, I assessed the tactile-driven plasticity using 2-photon calcium imaging in head-fixed anaesthetised or awake Fmr1-KO mice after undergoing the RWS paradigm. L2/3 neuronal responses in S1 were monitored via calcium (Ca²⁺) levels, which serve as a proxy for neuronal activity, using a fluorescent calcium indicator GCaMP6s. I successfully established and standardised a 2-photon calcium imaging data acquisition and analysis pipeline, recording neuronal activity in 6 wildtype (358 neurons) and 7 Fmr1-KO (347 neurons) anaesthetised mice, as well as 2 wildtype (137 neurons) and 6 Fmr1-KO (317 neurons) awake mice. Potentiation of neuronal responses following RWS was evident in Fmr1-KO mice under anaesthesia, however, it was less robust than in wildtype mice. Under awake conditions, there was no potentiation of neuronal responses in Fmr1-KO mice, but due to limited sample size of awake wildtype mice no comparison between the two genotypes could be made. Moreover, this impaired experience-dependent plasticity of L2/3 neurons in S1 seemed to be associated with an altered distribution of neuronal responsivity types between Fmr1-KO and wildtype mice, with Fmr1-KO mice exhibiting more neurons not responding to whisker stimulation. Lastly, I investigated whether the synaptic plasticity impairments observed in Fmr1-KO mice ex vivo are due to structural changes in key postsynaptic proteins. Immunohistochemical analysis of glutamate AMPA receptor (AMPAR) and postsynaptic density protein-95 (PSD95) synaptic puncta abundance in L2/3 neurons of S1 revealed no differences between wildtype and Fmr1-KO mice. This implies that AMPAR and PSD95 alterations do not underlie the disruption of synaptic plasticity observed in Fmr1-KO mice.