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

Abstract

Dravet syndrome 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 hypo-excitability 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 four-week-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 prior to seizure onset (P13-P17), after the period of highest seizure burden (P28-P32), and in adulthood (P58-P63). VPL and VPM synaptic activity showed 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 four weeks, 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.