Persistent input- and cell-type-specific synaptic alterations in the somatosensory thalamus of Dravet syndrome mice.

Dravet syndrome (DS) is an epileptic encephalopathy most often caused by loss-of-function mutations in the SCN1A gene, leading to haploinsufficiency of the voltage-gated sodium channel NaV1.1. Seizures begin during infancy and wane throughout childhood, but behavioral symptoms, including intellectual disability, motor impairments, and autistic features, remain through adulthood. Seizures primarily stem from inhibitory neuron hypoexcitability in the cortex, hippocampus, and thalamus, but circuit abnormalities underlying persistent behavioral symptoms are poorly understood. Prior work showed synapse dysfunction in thalamocortical neurons in 4-wk-old DS mice, but elucidating the timing and progression of these alterations is necessary to understand the disease stages that synapse dysfunction may contribute to circuit and behavioral phenotypes. We investigated synapse function in the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus before seizure onset (P13-P17), after the period of highest seizure burden (P28-P32), and in adulthood (P58-P63). VPL and VPM synaptic activity showed that excitatory input to the VPL was reduced after seizure onset, and this reduction persisted through adulthood, while VPM excitatory input was unaffected. We further showed a selective reduction in the function and number of excitatory sensory synapses in the VPL, with no change to cortical synapses. VPL and VPM neurons both showed inhibitory synapse dysfunction at 4 wk, which persisted in adult DS mice only in VPL neurons. These results revealed persistent input- and cell-type-specific alterations to thalamic synapses that develop after seizure onset and are maintained into adulthood, suggesting synaptic deficits could contribute to ongoing somatosensory thalamocortical circuit dysfunction and behavioral deficits in DS.NEW & NOTEWORTHY This study reveals that synaptic dysfunction in the somatosensory thalamus of Dravet syndrome (DS) mice emerges after seizure onset and persists into adulthood. Using electrophysiology and high-resolution imaging, we demonstrate a selective, persistent reduction of sensory input to VPL neurons, while cortical input remains intact. Inhibitory input to VPL thalamus is similarly impaired after seizure onset and persists in adulthood. These input- and cell-type-specific deficits may contribute to the enduring sensory and sleep impairments characteristic of DS.