Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction

Abstract

The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as "synaptopathy." Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.

Keywords: SNAREopathies; developmental and epileptic encephalopathy (DEE); drug resistant epilepsy; intellectual disability (ID); pre-synaptic mechanisms; synaptopathy.

Figure 1

Schematic representation of pre-synaptic proteins localization and their role in the synaptic functioning. Numerous proteins interact together and with the cellular membrane on the pre-synaptic terminal to release the neurotransmitters in the synaptic cleft. (1) Stx1, Snap25, and Vamp2 form the core of the SNARE complex, which is stabilized by Cplx1. (2) When the synaptic vesicle reaches the cellular membrane, Stxbp1 binds Stx1, starting the priming and the rapid fusion of the vesicle. (3) Sv2a, the only specific synaptic protein, interacts with Syt1 and induces neurotransmitter release. (4) On the contrary, Prrt2 inhibits this process by reducing the formation of the SNARE complex. (5) The disassembly of the SNARE complex is mediated by Snap proteins, (6) allowing the subsequent clathrin-mediated endocytosis, with the participation of the Dnm1. (7) This process is coordinated by several GTPases: Tbc1d24 regulates Rab35, while Rbns5 interacts with Rab4 and Rab5 to lead the empty synaptic vesicle toward the endosome for recycling.