Excitability of Sensory Cortex in Mouse Models of Fragile X Syndrome and Autism Spectrum Disorders
Distinct genetic forms of autism are hypothesized to share a common increase in excitation inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a systematic test of this hypothesis across 4 mouse models (Fmr1-/y, Cntnap2-/-, 16p11.2del/+, Tsc2+/-), focusing on somatosensory cortex. All mouse models with autism risk mutations showed reduced feedforward inhibition in layer 2/3 (L2/3) coupled with more modest, variable reductions in feedforward excitation, driving a common increase in E-I conductance ratio. Contrary to the classic, naïve prediction that increased E-I ratio drives spiking hyperexcitability, synaptic conductance modeling suggested that sensory inputs to this circuit would actually evoke stable or reduced firing in L2/3 in vivo. Indeed, spiking evoked by single whisker deflections was normal in the two strains whose modeling predicted stable synaptic depolarization (Cntnap2-/-, 16p11.2del/+) and was reduced in the Fmr1-/y mice, also matching that strain's modeling prediction. In addition, spiking of putative inhibitory neurons was reduced in each strain. Thus, increased E-I ratio does not necessarily yield increased spiking responses to simple sensory stimuli.
Stable or reduced spiking was surprising given the dramatically reduced inhibition observed in each strain. Thus, we tested whether the Fmr1-/y mouse exhibits excess spiking in response to multi-whisker sequences, which drive more spiking in S1 compared to single-whisker deflections and may thus engage a different synaptic E-I ratio. Total spiking to whisker sequences, and cross-whisker suppression, were reduced in Fmr1-/y mice. These effects were explained by reduced firing to the anatomically corresponding columnar whisker and increased tuning heterogeneity within each cortical column. This suggests that weak or heterogeneous sensory maps may underlie circuit abnormalities in disorders expressing autism spectrum behaviors.