ドラベ症候群モデルマウスにおける視床シナプスの入出力および細胞型特異的な発達変化

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 Na _V 1.1. Seizures begin during infancy and generally wane throughout childhood, but behavioral symptoms, such as 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. To understand when synaptic deficits develop and whether they could contribute to persistent thalamic dysfunction, 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). Recordings of VPL and VPM synaptic activity showed excitatory input to the VPL was significantly 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 into 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 that synaptic deficits could contribute to ongoing circuit dysfunction in DS.