Physiological and molecular impairment of PV circuit homeostasis in mouse models of autism

Abstract

Circuit dysfunction in autism may involve a failure of homeostatic plasticity. To test this, we studied parvalbumin (PV) interneurons which exhibit rapid homeostatic plasticity of intrinsic excitability following whisker deprivation in mouse somatosensory cortex. Brief deprivation reduces PV excitability by increasing Kv1 current to increase PV spike threshold. We found that PV homeostatic plasticity is disrupted in Tsc2+/-and Fmr1-/- models of autism. In wildtype mice, deprivation elevates the transcription factor ER81 which drives Kcna1 transcription, increasing Kv1.1 protein in the axon initial segment and soma. These molecular signatures of homeostasis were absent in Tsc2+/- and Fmr1-/-. Whisker enrichment increased PV excitability, but not in Tsc2+/-, indicating that homeostasis is lost bidirectionally. Deprivation reduced feedforward L4-L2/3 inhibition in wildtype but not Tsc2+/-mice. Thus, two autism models show a convergent loss of PV circuit homeostasis at physiological and molecular levels, potentially contributing to sensory processing impairments.