Synaptic Secretion and Beyond: Targeting Synapse and Neurotransmitters to Treat Neurodegenerative Diseases

Abstract

The nervous system is important, because it regulates the physiological function of the body. Neurons are the most basic structural and functional unit of the nervous system. The synapse is an asymmetric structure that is important for neuronal function. The chemical transmission mode of the synapse is realized through neurotransmitters and electrical processes. Based on vesicle transport, the abnormal information transmission process in the synapse can lead to a series of neurorelated diseases. Numerous proteins and complexes that regulate the process of vesicle transport, such as SNARE proteins, Munc18-1, and Synaptotagmin-1, have been identified. Their regulation of synaptic vesicle secretion is complicated and delicate, and their defects can lead to a series of neurodegenerative diseases. This review will discuss the structure and functions of vesicle-based synapses and their roles in neurons. Furthermore, we will analyze neurotransmitter and synaptic functions in neurodegenerative diseases and discuss the potential of using related drugs in their treatment.

Figure 1

Secretory process and recycling of synaptic vesicles. The synaptic vesicle cycle consists of exocytosis, endocytosis, and recycling. Synaptic vesicles filled with neurotransmitters are docked to the presynaptic active zone by translocation, where the vesicles undergo a priming reaction. When they fuse with the presynaptic membrane, the neurotransmitters are released. Subsequently, synaptic vesicles undergo endocytosis and recycling.

Figure 2

The working model of CAPS–Munc13 in vesicle exocytosis. (A) In the resting state, CAPS-1 is first located on the cytoplasmic membrane; Munc13-1 cannot bind to Munc18-1/syntaxin-1 complex, resulting in the anchored DCVs and the inability of SVs to enter the vesicle priming stage. (B) Under the action of intracellular Ca²⁺, Munc13-1 protein that successfully escapes the inhibition of CAPS-1 can bind to Munc18-1/syntaxin-1 complex and catalyze the opening of syntaxin-1. (C) When the syntaxin-1 protein is open and SNAP-25 exists, CAPS-1 binds to syntaxin-1/SNAP-25 complex to further stabilize the open state of syntaxin-1 then promotes binding with Synaptobrevin-2 to form the SNARE complex. (D) With the influx of extracellular Ca²⁺, vesicle membrane fusion can occur quickly and effectively; then, the release of neurotransmitters occurs.

Figure 3

Proposed mechanisms of action of antiepileptic drugs (AEDs) at excitatory and inhibitory synapse. Clinically approved AEDs display a spectrum of mechanisms of action with effects on both inhibitory (left-hand side) and excitatory (right-hand side) nerve terminals. Several synaptic targets of drugs are illustrated, including voltage-gated ion channels (e.g., Na⁺, K⁺, and Ca²⁺), the α 2δ subunit of the voltage-gated Ca²⁺ channel, vesicular proteins (e.g., SV2A), GABA transporters (GAT-1), GABA receptors, and AMPA receptors.