Circuit level defects in the developing neocortex of fragile X mice

Subtle alterations in how cortical network dynamics are modulated by different behavioral states could disrupt normal brain function and underlie symptoms of neuropsychiatric disorders, including fragile X syndrome (FXS). Using two-photon calcium imaging and electrophysiology we recorded spontaneous neuronal ensemble activity in mouse somatosensory cortex. Unanesthetized Fmr1(–/–) mice exhibited abnormally high synchrony of neocortical network activity, especially during the first two postnatal weeks. Neuronal firing rates were 3-fold higher in Fmr1(–/–) mice during whole-cell recordings manifesting Up/Down states (slow wave sleep, quiet wakefulness), likely due to a higher firing probability during Up states. Combined EEG/calcium imaging experiments confirmed that neurons in mutant mice have abnormally high firing and synchrony during sleep. We conclude that cortical networks in FXS are hyperexcitable in a brain state-dependent manner during a critical period for experience-dependent plasticity. These state-dependent network defects could explain the intellectual, sleep and sensory integration dysfunctions associated with FXS.