PT - JOURNAL ARTICLE AU - McCabe, Matthew P. AU - Shore, Amy N. AU - Frankel, Wayne N. AU - Weston, Matthew C. TI - Altered Fast Synaptic Transmission in a Mouse Model of DNM1-Associated Developmental Epileptic Encephalopathy AID - 10.1523/ENEURO.0269-20.2020 DP - 2021 Mar 01 TA - eneuro PG - ENEURO.0269-20.2020 VI - 8 IP - 2 4099 - http://www.eneuro.org/content/8/2/ENEURO.0269-20.2020.short 4100 - http://www.eneuro.org/content/8/2/ENEURO.0269-20.2020.full SO - eNeuro2021 Mar 01; 8 AB - 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” (Dnm1Ftfl), 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 Dnm1Ftfl variant is thought to encode a dominant negative DNM1 protein; however, the effects of the Dnm1Ftfl 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 [excitation of excitation (E-E), inhibition of inhibition (I-I), E-I, I-E]. 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, because of a smaller pool of releasable SVs. In addition to these synaptic alterations, Dnm1Ftfl neurons degenerated later in development, although their activity levels were reduced, suggesting that Dnm1Ftfl may impair synaptic transmission and neuronal health through distinct mechanisms.