Neurotransmitters-Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System

Abstract

Neurotransmitters are molecules that amplify, transmit, and convert signals in cells, having an essential role in information transmission throughout the nervous system. Hundreds of such chemicals have been discovered in the last century, continuing to be identified and studied concerning their action on brain health. These substances have been observed to influence numerous functions, including emotions, thoughts, memories, learning, and movements. Thus, disturbances in neurotransmitters' homeostasis started being correlated with a plethora of neurological and neurodegenerative disorders. In this respect, the present paper aims to describe the most important neurotransmitters, broadly classified into canonical (e.g., amino acids, monoamines, acetylcholine, purines, soluble gases, neuropeptides) and noncanonical neurotransmitters (e.g., exosomes, steroids, D-aspartic acid), and explain their link with some of the most relevant neurological conditions. Moreover, a brief overview of the recently developed neurotransmitters' detection methods is offered, followed by several considerations on the modulation of these substances towards restoring homeostasis.

Keywords: neurodegenerative disorders; neurological disorders; neurotransmitters; neurotransmitters detection; neurotransmitters modulation.

Figure 1

Classification of neurotransmitters.

Figure 2

Schematic representation of glutamate homeostasis at the tripartite glutaminergic synapse. Reprinted from an open-access source [12]. Abbreviations: SNAT—sodium-coupled neutral amino acid transporter; Sxc antiporter—cystine/glutamate antiporter system xc; EAAT—excitatory amino acid transporter; NMDA—N-methyl-d-aspartate; AMPA—alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; VGLUT—vesicular glutamate transporter; VRAC—volume regulated anion channels; TREK—TWIK related potassium channel; BEST—bestrophin; ROS—reactive oxygen species; GSH—glutathione.

Figure 3

(A) Schematic representation of the function of neuronal exosomes as neuromodulators. In neurons, MVBs fuse with the plasma membrane without being restricted to the synaptic specialization and release exosomes into extracellular spaces, including the synaptic cleft. Through their various cargos, exosomes regulate synaptic plasticity. (B) The proposed models for neuronal exosomes as neurotransmitters. In response to action potentials, exosomes are released from the presynaptic neuron. As they carry neuropeptides and other ligands, exosomes activate GPCRs and downstream signaling cascade, leading to Ca²⁺ release from ER. Reprinted from an open-access source [1]. Abbreviations: AMPAR—alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; DCV—dense core vesicles; ER—endoplasmic reticulum; GPCR—G protein-coupled receptors; IP₃—inositol 1,4,5-triphosphate; IP₃R—IP₃ receptor; MVB—multivesicular bodies; PLC—phospholipase C; sNT—small neurotransmitter; SV—synaptic vesicles; Syt4—Synaptotagmin-4.

Figure 4

Schematic representation of the dopamine hypothesis. Created based on information from [102,103].

Figure 5

Glutamate and dopamine-related striatal events—focus on astrocytes and microglia functions in (A) healthy state, (B) Parkinson’s disease (PD) condition. Grey box: fronto-basal circuits involved in the modulation of voluntary movements and impaired connectivity caused by dopamine degeneration in PD. Reprinted from an open-access source [15]. Abbreviations: AMPA—alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CTX—cerebral cortex; Cys—cysteine; EEAT—excitatory amino acid transporter; GPe—external segment of the globus pallidus; GPi—internal segment of the globus pallidus; GSH—glutathione; mGluR—metabotropic glutamate receptor; NMDA—N-methyl-D-aspartate; SNpc—substantia nigra pars compacta; SPN—spiny projection neuron; STN—subthalamic nucleus; xC—cysteine–glutamate exchange system.