Roles of Gasotransmitters in Synaptic Plasticity and Neuropsychiatric Conditions

Abstract

Synaptic plasticity is important for maintaining normal neuronal activity and proper neuronal functioning in the nervous system. It is crucial for regulating synaptic transmission or electrical signal transduction to neuronal networks, for sharing essential information among neurons, and for maintaining homeostasis in the body. Moreover, changes in synaptic or neural plasticity are associated with many neuropsychiatric conditions, such as schizophrenia (SCZ), bipolar disorder (BP), major depressive disorder (MDD), and Alzheimer's disease (AD). The improper maintenance of neural plasticity causes incorrect neurotransmitter transmission, which can also cause neuropsychiatric conditions. Gas neurotransmitters (gasotransmitters), such as hydrogen sulfide (H₂S), nitric oxide (NO), and carbon monoxide (CO), play roles in maintaining synaptic plasticity and in helping to restore such plasticity in the neuronal architecture in the central nervous system (CNS). Indeed, the upregulation or downregulation of these gasotransmitters may cause neuropsychiatric conditions, and their amelioration may restore synaptic plasticity and proper neuronal functioning and thereby improve such conditions. Understanding the specific molecular mechanisms underpinning these effects can help identify ways to treat these neuropsychiatric conditions.

Figure 1

Transmission of signals through the synaptic junctions. Signals or impulses at the presynaptic terminal trigger the release of glutamate that binds to glutamate receptors at the postsynaptic membrane. Activation of α-amino-3-hydroxy-5-methyl-isoxazole-4-propanoic acid (AMPA) as well as kainate receptors which subsequently transport sodium ions that trigger postsynaptic depolarization. As membrane potential changes, it initiates the release of magnesium ions which blocks N-methyl-D-aspartate (NMDA) receptors. Influx of calcium via NMDA channels sets off a chain of events which establish long-term potentiation. Kainate receptors at the presynaptic end also seem to facilitate synaptic transmission at particular synapses by accumulating neurotransmitter release.

Figure 2

Role of gas neurotransmitters in neuropsychiatric diseases. The three gas neurotransmitters such as hydrogen sulfide (H₂S), nitric oxide (NO), and carbon dioxide (CO) have a role in neuropsychiatric conditions such as major depressive disorder (MDD), schizophrenia (SCZ), bipolar disorder (BD), and Alzheimer's disease (AD) to maintain proper synaptic plasticity as well as neural homeostasis. H₂S has a role in tropomyosin receptor kinase B (TrKB) and glutamate as well as mechanistic targets of rapamycin (mTOR) signaling pathways, and it activates the TrKB-mTOR signaling pathway as well as synaptic protein in MDD. NO has a role in the regulation of altered synthesis of nNOS as well as upregulates Akt and cyclic AMP (cAMP) response element binding (CREB) protein which restores function in N-methyl-D aspartate (NMDA) receptor and reduces Ca²⁺ influx in schizophrenia, MDD, and AD. CO has a role in NMDA-induced calcium ion (Ca²⁺) influx or excitotoxicity via S-nitrosylation of antiglutamate receptor NMDAR2A (NR2A) subunit and restores synaptic function in AD and SCZ. However, these gas neurotransmitters work on various ways to maintain or restore synaptic plasticity in these neuropsychiatric diseases.