SNARE complex in developmental psychiatry: neurotransmitter exocytosis and beyond

Abstract

Multiple biological processes throughout development require intracellular vesicular trafficking, where the SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors) complex plays a major role. The core proteins forming the SNARE complex are SNAP-25 (synaptosomal-associated protein 25), VAMP (vesicle-associated membrane protein) and Syntaxins, besides its regulatory proteins, such as Synaptotagmin. Genes encoding these proteins (SNAP25, VAMP1, VAMP2, STX1A, SYT1 and SYT2) have been studied in relation to psychiatric disorders susceptibility. Here, we review physiological aspects of SNARE complex and genetic association results reported for attention deficit hyperactivity disorder, both in children and adults, autism spectrum disorders, major depressive disorder, bipolar disorder and schizophrenia. Moreover, we included findings from expression, pharmacogenetics and animal model studies regarding these clinical phenotypes. The overall scenario depicted here suggests that the SNARE complex may exert distinct roles throughout development, with age-specific effects of genetic variants in psychiatric disorders. Such perspective should be considered in future studies regarding SNARE complex genes.

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

“…Among these 6 variants, a homozygous missense mutation in VAMP1 (NM_014231: c.146G>C; p.Arg49Pro; see Fig 1D) emerged as the most likely explanation for the disease pathogenesis, as supported by protein function (the mutation affects a conserved amino acid within the active domain of the protein),14, 15 expression and role of this gene in the NMJ,12, 16 and the homozygous mutation identified in the patients from Family 1 presenting the same phenotype (see Fig 1C–G).…”

“…Synaptobrevins (eg, Vamp1, Vamp2), syntaxins, and the synaptosomal‐associated protein Snap25 represent the main components of the SNARE (soluble N ‐ethylmaleimide‐sensitive factor attachment protein receptors) complex, which is involved in docking and fusion of synaptic vesicles with the presynaptic membrane at the central and the neuromuscular synapses 15, 16. Proteins belonging to this complex are involved in vesicle docking through the evolutionarily conserved active v‐SNARE coiled coil homology domain and present high sequence similarity across the different SNAREs 17, 18, 19…”

MicroRNA and mesial temporal lobe epilepsy with hippocampal sclerosis: Whole miRNome profiling of human hippocampus

“…In close relationship with axon guidance is neurotrophin signaling, which uses a family of trophic factors (neurotrophins) to govern the differentiation, survival, and remodeling of neural cells with a possible effect on excitability . Sphingolipid signaling and SNARE interactions in vesicular transport facilitate the intracellular trafficking processes essential for different biological events including neuronal network development and maintenance, and their imbalance could result in serious neurological disorders (e.g., schizophrenia, Alzheimer disease, epilepsy) . All aforementioned pathways have been previously studied in connection with mTLE+HS and/or other subtypes of epilepsy.…”

“…38 Sphingolipid signaling and SNARE interactions in vesicular transport facilitate the intracellular trafficking processes essential for different biological events including neuronal network development and maintenance, and their imbalance could result in serious neurological disorders (e.g., schizophrenia, Alzheimer disease, epilepsy). 39,40 All aforementioned pathways have been previously studied in connection with mTLE+HS and/or other subtypes of epilepsy. However, these in silico analyses need to be confirmed by further functional experiments on cell cultures and animal models.…”

Parvalbumin-containing GABA cells and schizophrenia: experimental model based on targeted gene delivery through adeno-associated viruses

“…TeLc is a bacterial neurotoxin that acts intracellularly (Gaisano et al ., 1994), by cleaving the vesicle-associated membrane protein-2 (VAMP-2). The vesicle-associated membrane protein (VAMP) family is comprised of seven members involved in vesicle fusion and thus forms an integral part of the core of the soluble N -ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex (for review, see Cupertino et al ., 2016). Therefore, TeLc-affected neurones are unable to complete vesicle docking for transmitter release and our viral transfection tool constitutes a permanent inactivation of transmission of the cell, while the external inputs remain intact.…”