Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders

Abstract

There have been no recent advances in drug development for mood disorders in terms of identifying drug targets that are mechanistically distinct from existing ones. As a result, existing antidepressants are based on decades-old notions of which targets are relevant to the mechanisms of antidepressant action. Low rates of remission, a delay of onset of therapeutic effects, continual residual depressive symptoms, relapses, and poor quality of life are unfortunately common in patients with mood disorders. Offering alternative options is requisite in order to reduce the individual and societal burden of these diseases. The glutamatergic system is a promising area of research in mood disorders, and likely to offer new possibilities in therapeutics. There is increasing evidence that mood disorders are associated with impairments in neuroplasticity and cellular resilience, and alterations of the glutamatergic system are known to play a major role in cellular plasticity and resilience. Existing antidepressants and mood stabilizers have prominent effects on the glutamate system, and modulating glutamatergic ionotropic or metabotropic receptors results in antidepressant-like properties in animal models. Several glutamatergic modulators targeting various glutamate components are currently being studied in the treatment of mood disorders, including release inhibitors of glutamate, N-methyl-D-aspartate (NMDA) antagonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) throughput enhancers, and glutamate transporter enhancers. This paper reviews the currently available knowledge regarding the role of the glutamatergic system in the etiopathogenesis of mood disorders and putative glutamate modulators.

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

After uptake by glial cells, glutamate is transformed into glutamine, which in turn returns to the presynaptic neuron to be reconverted into glutamate by the enzyme glutaminase or synthesized de novo from glucose via the Krebs cycle (not shown). Glu is packaged into presynaptic vesicles and released in the synapse to target diverse postsynaptic receptors, including both ionotropic receptors — AMPA, NMDA, and kainate receptors — as well as mGluRs. These and other promising therapeutic targets are described as presynaptic (I–V), glial (VI, VII) and postsynaptic Glu targets (VIII–XII): I- Regulation of presynaptic vesicular release of Glu. Glu is packaged into presynaptic vesicles by the VGLUTs, which critically modulates glutamate concentration in the synaptic vesicles and its consequent release in the synaptic cleft. II- Voltage-dependent Na+ channel regulation that controls Glu release. Attenuation of voltage-activated sodium channel activity reduces the exaggerated action potential in the presynaptic terminal, thus limiting Glu release. III- Presynaptic voltage-operated release of Glu regulates calcium accumulation in the synaptic terminal at the same time that it controls glutamate release. IV- Up- and down-regulation of presynaptic group II mGluR modulation have anxiolytic and antidepressant activity. V- Presynaptic vesicular Glu release from the neuron is directly regulated by the SNARE proteins. VI- Direct effects of extrasynaptic Glu release from glial cells. VII- Glu clearance from the extracellular space via high-affinity EAATs presented mainly in glial cells, which may have altered expression, thus facilitating accumulation of Glu in the synapse. VIII- AMPA receptor regulation. Downregulation in AMPA receptor expression in different brain areas is found in mood disorders, which may be reversed by treatment with antidepressants, which also increase AMPA receptor trafficking. IX- Synaptic NMDA receptor regulatory effects. Altered expression and functional polymorphisms have been demonstrated in mood disorders, which may increase the NMDA-receptor-mediated Ca2+ influx and Glu levels. Downregulating these targets and thus decreasing Glu levels may be beneficial in the therapeutics of mood disorders. X- Group I mGluR modulation. XI- Regulation in the expression and function of PSD proteins, also comprising glutamate receptors and anchor proteins, may represent an important therapeutic target because centralized Glu effects are modulated by diverse receptor subtypes and interactions with various signaling and scaffolding proteins in the PSD. XII- extrasynaptic NMDA receptor modulation. AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid); Glu (Glutamate); Gly (Glycine); EAATs (excitatory amino-acid transporters); mGluRs (metabotropic Glu receptors); NMDA (N-methyl-D-aspartate); PSD (postsynaptic density); PSVR (presynaptic voltage-operated release); SNARE (soluble N-ethylmaleimide-sensitive factor attachment receptor); VGLUTs (vesicular Glu transporters);