Altered fast synaptic transmission in a mouse model of DNM1-associated developmental epileptic encephalopathy

Abstract

Developmental epileptic encephalopathies (DEEs) are severe seizure disorders that occur in infants and young children, characterized by developmental delay, cognitive decline, and early mortality. Recent efforts have identified a wide variety of genetic variants that cause DEEs. Among these, variants in the DNM1 gene have emerged as definitive causes of DEEs, including infantile spasms and Lennox-Gastaut syndrome. A mouse model of Dnm1-associated DEE, known as “Fitful” (Dnm1^Ftfl), recapitulates key features of the disease, including spontaneous seizures, early lethality, and neuronal degeneration. Previous work showed that DNM1 is a key regulator of synaptic vesicle (SV) endocytosis and synaptic transmission, and suggested that inhibitory neurotransmission may be more reliant on DNM1 function than excitatory transmission. The Dnm1^Ftfl variant is thought to encode a dominant negative DNM1 protein, however, the effects of the Dnm1^Ftfl variant on synaptic transmission are largely unknown. To understand these synaptic effects, we recorded from pairs of cultured mouse cortical neurons and characterized all four major connection types (E-E, E-I, I-E, I-I). Miniature and spontaneous EPSCs and IPSCs were larger, but less frequent, at all Dnm1Ftfl synaptic types, and Dnm1Ftfl neurons had reduced expression of excitatory and inhibitory SV markers. Baseline evoked transmission, however, was reduced only at inhibitory synapses onto excitatory neurons, due to a smaller pool of releasable SVs. In addition to these synaptic alterations, Dnm1Ftfl neurons degenerated later in development, even though their activity levels were reduced, suggesting that Dnm1Ftfl may impair synaptic transmission and neuronal health through distinct mechanisms.

Significance Statement Recent work has identified genetic variants in DNM1 as among the more common causes of developmental epileptic encephalopathies (DEEs), but the physiological consequences of its mutation are unclear. Here, we make use of an in vitro model of Dnm1-associated DEE to determine the effects of a Dnm1 variant on the four main cortical synapse types. The variant caused both synapse-specific and synapse-wide alterations, and decreased neuronal activity. Despite this, neurons still degenerated after two weeks in vitro, suggesting that neuronal degeneration in these mice may be independent of seizures, and that stopping seizures may do little to mitigate key features of DEEs.