Genetic disorders of neurotransmitter release machinery

Abstract

Synaptic neurotransmitter release is an evolutionarily conserved process that mediates rapid information transfer between neurons as well as several peripheral tissues. Release of neurotransmitters are ensured by successive events such as synaptic vesicle docking and priming that prepare synaptic vesicles for rapid fusion. These events are orchestrated by interaction of different presynaptic proteins and are regulated by presynaptic calcium. Recent studies have identified various mutations in different components of neurotransmitter release machinery resulting in aberrant neurotransmitter release, which underlie a wide spectrum of psychiatric and neurological symptoms. Here, we review how these genetic alterations in different components of the core neurotransmitter release machinery affect the information transfer between neurons and how aberrant synaptic release affects nervous system function.

Keywords: Munc13; SNAP25; SNAREopathy; neurogenetic disorders; synapse; synaptobrevin; synaptotagmins; syntaxin.

FIGURE 1

Overview of the synaptic vesicle release. (A) Synaptic vesicles are docked to the presynaptic terminal, followed by priming and fusion that is mediated by the components of the synaptic release machinery. (B) Graphical depiction of synaptic vesicle release induced by the arrival of an action potential to the presynaptic terminal, preceded by priming of the docked synaptic vesicles. Cplx, complexin; Syt1, synaptotagmin-1; Syb2, synaptobrevin-2. (C) Graphical depiction representing different modes of synaptic vesicle release and their representative electrophysiological traces, that comprise evoked (synchronous and asynchronous) and spontaneous release.

FIGURE 2

Overview of the pathogenic Syb2 and SNAP25 variants’ effects on synaptic vesicle release. (A) Summary of all reported pathogenic Syb2 (NCBI Accession #: AAF15551.1) variants and the most common clinical phenotype of the patients harboring these variants (Variants are color-coded based on their effects on the protein. Nonsense mutations are presented in red, missense mutations are presented in black, frameshift mutations are presented in blue, and deletions/insertions are presented in orange). (B) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of Syb2. (C) Graphical summary of the findings explaining aberrant forms of vesicle fusion and neurotransmission caused by different Syb2 variants (S75P, G73W, and R56L). (D) Summary of all reported pathogenic SNAP25 (NCBI Accession #: NP_001309838.1) variants and the most common clinical phenotype of the patients harboring these variants (Variants are color-coded based on their effects on the protein. Nonsense mutations are presented in red, missense mutations are presented in black, and frameshift mutations are presented in blue). (E) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of SNAP25. (F) Graphical summary of the findings explaining the effects of different SNAP25 variants (N-terminal, C-terminal, or Syt1-interface variants) on different modes of neurotransmitter release.

FIGURE 3

Overview of the pathogenic Stx1b and Syt1 variants’ effects on synaptic vesicle release. (A) Summary of all reported pathogenic Stx1b (NCBI Accession #: NP_443106.1) variants and the most common clinical phenotype of the patients harboring these variants (Variants are color-coded based on their effects on the protein. Nonsense mutations are presented in red, missense mutations are presented in black, frameshift mutations are presented in blue, and deletions/insertions are presented in orange). (B) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of Stx1a and/or Stx1b. (C) Graphical depiction showing that the epileptiform phenotype caused by Stx1b-knockdown in zebrafish cannot be rescued by the V216E variant indicating loss-of-function. (D) Graphical summary of the findings explaining the effects of different Stx1b variants (K45indel, V216E, and G226E) on different modes of neurotransmitter release and their mechanism of action. (E) Summary of all reported pathogenic Syt1 (NCBI Accession #: AAH58917.1) variants and the most common clinical phenotype of the patients harboring these variants (Variants are color-coded based on their effects on the protein. Missense mutations are presented in black, and duplications are presented in orange). (F) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of Syt1. (G) Graphical summary of the findings explaining the effects of different Syt1 variants (D4G, D366E, I368T, and M303K) on different modes of neurotransmitter release.

FIGURE 4

Overview of the pathogenic Cplx1, Munc18-1, and Munc13 variants’ effects on synaptic vesicle release. (A) Summary of all reported pathogenic Cplx1 (NCBI Accession #: NP_006642.1) variants and the most common clinical phenotype of the patients harboring these variants (Variants are color-coded based on their effects on the protein. Nonsense mutations are presented in red, missense mutations are presented in black, and frameshift mutations are presented in blue). (B) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of Cplx1 and/or Cplx 2 and upon triple knockout of Cplx1/2/3. (C) Summary of the most common clinical phenotype of the patients harboring pathogenic Munc18-1 (NCBI Accession #: NP_001361240.1) variants (STXBP1 encephalopathies). (D) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of Munc18-1. (E) Graphical summary of the findings explaining the loss-of-function outcomes of most Munc18-1 variants and the gain-of-function effects of L446F variant. (F) Summary of all reported pathogenic Munc13 (NCBI Accession #: AAC19406.1) variants and the most common clinical phenotype of the patients harboring these variants (Variants are color-coded based on their effects on the protein. Nonsense mutations are presented in red, missense mutations are presented in black, and frameshift mutations are presented in blue). (G) Graphical depiction demonstrating the changes in synaptic vesicle release upon genetic deletion of Munc13-1, Munc13-2, Munc13-3, and double knockout of Munc13-1/2. (H) Graphical summary of the findings explaining the effects of different Munc13 variants on different modes of neurotransmitter release (Q108X and P814L). (I) Munc13 variants are not only associated with early-onset neurobehavioral symptoms as the pathogenic variants in the other components of the release machinery, but also are associated with some complex diseases like ALS, FTS, and schizophrenia that develop later in life.