The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders

Abstract

Bipolar disorder and major depressive disorder are common, chronic, and recurrent mood disorders that affect the lives of millions of individuals worldwide. Growing evidence suggests that glutamatergic system dysfunction is directly involved in mood disorders. This article describes the role of the "tripartite glutamatergic synapse," comprising presynaptic and postsynaptic neurons and glial cells, in the pathophysiology and therapeutics of mood disorders. Glutamatergic neurons and glia directly control synaptic and extrasynaptic glutamate levels/ release through integrative effects that target glutamate excitatory amino acid transporters, postsynaptic density proteins, ionotropic receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA], N-methyl-D-aspartate [NMDA], and kainate), and metabotropic receptors. This article also explores the glutamatergic modulators riluzole and ketamine, which are considered valuable proof-of-concept agents for developing the next generation of antidepressants and mood stabilizers. In therapeutically relevant paradigms, ketamine preferentially targets postsynaptic AMPA/NMDA receptors, and riluzole preferentially targets presynaptic voltage-operated channels and glia.

Figure 1. Pathophysiological basis and potential therapeutic targets for mood disorders involving glutamatergic neurotransmission

Ketamine preferentially targets postsynaptic AMPA/NMDA receptors, while riluzole’s antidepressant effects occur through direct regulation, mostly at presynaptic voltage-operated channels and glia. All potential targets for new, improved glutamatergic agents are described below. Presynaptic targets: Before release, Glu is packaged into vesicles by VGLUTs, which control glutamate concentration produced in the synaptic vesicles (Target I). Activation of voltage-gated sodium channels (Target II) and VOCCs (Target III) depolarizes the plasma membrane, allowing for the influx of sodium (through depolarization of axon terminals) and calcium (through interaction with the SNARE proteins) (Target IV), leading to the fusion of synaptic vesicles and the consequent release of Glu into the synaptic cleft. The type II mGluRs (mGlu2/3) are also present presynaptically (Target V), and may directly limit the synaptic release of Glu. These mGluRs also mediate feedback inhibition of Glu release, thus decreasing the activity of Glu synaptic terminals when the activation of presynaptic receptors reaches a certain level. Glia: Glu can also be directly released from glial cells, regulating synaptic activity pre-and post-synaptically (Target VI). After its release, large amounts of Glu are rapidly distributed across the synaptic cleft, where it can bind to glutamate receptors in the postsynaptic regions. The remaining unbound Glu is rapidly removed from the synaptic cleft to the presynaptic neuron mostly by glia and EAATs. The glial transporters EAAT1 (also known in rodents as GLAST) and EAAT2 (or GLT-1) are essential for blocking pathological increases in Glu levels (Target VII). Glial Glu transporter expression is upregulated by neuronal activity. Notably, the expression of Glu transporters by glial cells and their anatomical arrangement within the synaptic cleft can be dynamically and reversibly modified, and can directly regulate their ability to scavenge Glu. Postsynaptic neuron: AMPARs (GluR1-4) mediate fast Glu neurotransmission and play a major role in learning and memory through critical regulation of calcium metabolism, plasticity, and oxidative stress. When activated, these receptors open the transmembrane pore, thus allowing the influx of sodium and the consequent depolarization of the neuronal membrane (Target VIII). The NMDAR channel includes the subunits NR1, NR2 (NR2A—NR2D), and NR3 (NR3A and NR3B). Glu’s binding sites have been described mostly in the NR2 subunit, whereas the NR1 subunit is the site for its co-agonist, glycine. NR2A and NR2B subunit receptors are both highly expressed in brain areas implicated in mood regulation, but NMDA receptors containing NR2A mediate faster neurotransmission than NR2B receptors (Target IX). The mGluRs include eight receptor subtypes (mGluR1 to mGluR8) classified in three groups (I-III) based on their sequence homology and effectors. The mGluRs in group I, including mGluR1 and mGluR5, stimulate the breakdown of phosphoinositide phospholipids in the cell plasma membrane. mGluRs in Groups II (including mGLuR2/3) and III (including mGluRs 4, 6, 7, and 8) limit the generation of cAMP by activating inhibitory G-proteins.While Group I receptors are coupled to the phospholipase C signal transduction pathway, Group II and III mGluRs are both coupled in an inhibitory manner to the adenylyl cyclase pathway, which is involved in regulating the release of Glu or other neurotransmitters such as GABA (Target X). KARs are involved in excitatory neurotransmission by activating postsynaptic receptors, and in inhibitory neurotransmission by modulating GABA release. There are five types of KAR subunits: GluR5 (GRIK1), GluR6 (GRIK2), GluR7 (GRIK3), KA1 (GRIK4), and KA2 (GRIK5). GluR5-7 can form heteromers; KA1 and KA2 can only form functional receptors by binding with one of the GluR5-7 subunits. KARs have a more limited distribution in the brain than AMPARs and NMDARs, and their function is not well defined; they are believed to affect synaptic signaling and plasticity less than AMPARs (Target XI). Cytoplasmic PSD-enriched intracellular molecules (e.g. PSD93) interact with Glu receptors at the synaptic membrane to modulate receptor activity and signal transduction. PSD95 and similar scaffolding molecules link the NMDARs with intracellular enzymes that regulate signaling, and also provide a physical connection between diverse neurotransmitter systems to synchronize information from different effectors (Target XII).