**5. Synaptic vesicles**

Alterations in neurotransmission and its components, such as synaptic vesicles seem to be one of the keys in neurological disorders. Abnormalities in synaptic vesicle endocytosis and recycling may contribute with this type of disorder. Exoendocytic cycling of synaptic vesicles, which are organelles of 40 nm in diameter, is involved in neurotransmitter release. Hundreds of synaptic vesicles, filled with neurotransmitters are found in each presynaptic nerve terminal. When presynaptic plasma membranes depolarize, Ca2þ-channels open and calcium flows into the nerve terminal, triggering the exocytosis of synaptic vesicles and releasing their neurotransmitters into the synaptic cleft. Calcium binds to synaptotagmin, and after exocyto‐ sis, vesicles are re-endocytosed, recycled, and refilled with neurotransmitters. Recycling can occur by multiple parallel pathways, either by fast recycling via local reuse of vesicles, or by slower recycling through an intermediate endosomal [137]. Also, a critical step in presynaptic differentiation is the clustering of synaptic vesicles near neurotransmitter release sites, the active zone, where vesicle fusion and exocytosis of neurotransmitters occur. Synaptic vesicles at presynaptic terminals store neurotransmitters from presynaptic neurons such as gammaaminobutyric acid (GABA) and glutamate [133].

Many presynaptic molecules are involved in the regulation of synaptic vesicle release, including CAMs. The family of adaptor protein (AP) complexes, AP-1, AP-2, AP-3 and AP-4 mediates various types of vesicle formation and selection of cargo molecules for inclusion in these vesicles. The synaptic vesicle process involves AP-2/clathrin-mediated endocytosis [133]. The structural composition of synapses may be altered by mutations or deletions in other scaffold proteins, such as those of the Shank family, neurexin and NLS. These changes may result in an altered number of receptors such as mGluR receptors or changes in the composition of NMDA and AMPA, and affect component signaling in PSD. Dysregulation in the synapse morphology induced by structural alterations and disturbed signaling might converge and lead to disrupted long-term potentiation (LTP) formation and plasticity, and a specific decrease in excitatory signaling by various genetic mutations, environmental factors, or immune system alterations, which would lead to an imbalance in inhibition and excitation as a likely cause of autism [26].

The main excitatory neurotransmitter in the brain, glutamate, modulates the neuronal formation and synaptic strength in the early phases of development due to its role in neuronal plasticity and cognitive functioning [88]. Glutamate receptors are diffused throughout the brain, in the cerebellum and hippocampus, regions implicated in ASD pathogenesis [25]. Genetic alterations in glutamate signaling have been found in association with ASD through candidate gene screening and genetic association studies and an imbalance in excitation and inhibition with glutamate signaling is proposed as a mechanism involved in ASD during the early development stages, between one and three years of age [112].

There are two types of glutamate receptors, metabotropic and ionotropic. Metabotropic glutamate receptors (mGluR) are G-protein coupled receptors involved in intracellular signal transduction and can be divided into three groups: Groups I (mGluR1 and mGluR5), II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7 and mGluR8). Group I receptors activate phospholipase C. Groups II and III are negatively linked to cyclic adenosine 3′,5′ monophosphate (AMP) production, but they differ in agonist selectivity. Two Group III receptors, mGluR7 and mGluR8, are located within the presynaptic grid, whereas mGluR3 and mGluR2 are located on the preterminal axons. Ionotropic glutamate receptors form ligandgated ion channels (LGICs) and are labeled according to their prototypical agonists: NMDA, AMPA and kainate [25].

Some studies have focused on the endocytosis, docking, priming, fusion and recycling processes that may play a role in intellectual disability and ASD, but the functions of several vesicle components remain unidentified and more studies are needed to understand these processes [133].
