Molecular Mechanisms of Glutamatergic Synapse Function and Dysfunction

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system. Glutamatergic synaptic transmission is of fundamental importance in relaying sensory information as well as driving higher cognitive functions such as learning and memory and emotional regulation. Not surprisingly, these synapses are implicated in several neurological and psychiatric disorders such as stroke, movement disorders, intellectual disability, dementia, mood and psychotic disorders. Therefore, their function is of utmost relevance to mental health and they continue to be one of the major targets for developing therapeutics.

Glutamate acts through both ionotropic and metabotropic receptors that couple to a diverse array of intracellular signaling and scaffolding molecules which regulate vital cellular processes including development, survival and plasticity. Maturation of neural circuits is based on maturation of synaptic connections that requires appropriate synaptic expression of specific glutamate receptor subtypes during development. Aberrant synapse maturation contributes to neurodevelopmental disorders, and anomalies in synapse structure and density observed in such disorders are linked to inappropriate glutamatergic signaling.

A central player in glutamatergic signaling is calcium, which activates prominent downstream effector molecules with both transient and long-lasting consequences ranging from induction of synaptic plasticity on one hand to triggering neuronal death on the other. A key event, downstream from glutamatergic signaling, is the local regulation of protein synthesis (also known as mRNA translation). Local synthesis of proteins is central for developmental and plasticity events. Moreover, post-translational modifications, such as phosphorylation, ubiquitination, palmitoylation and protein-protein interactions dynamically modulate the signaling complexes mediating such events. Recent advances in imaging (super-resolution and cryo-EM) and biochemical methods (proximity labeling, liquid-liquid phase separation analyses) are increasingly revealing the topography of glutamatergic signaling at an individual synapse in unprecedented spatial resolution. In addition, the interplay between glutamate and different neuromodulators determines the synaptic output and associated animal behavior thereby constituting another major area of research interest.

Notably, the signaling pathways operating at the glutamatergic synapse are often hijacked by disease-causing agents. Glutamatergic synaptic dysfunction is a leading hypothesis for the pathogenesis of several major neuropsychiatric disorders and understanding the molecular mechanisms of glutamatergic synapse function is essential to develop effective therapeutic interventions. Since the cloning of the glutamate receptors over 30 years ago, an impressive amount of molecular details about their significant role and regulation at the synapse have accumulated, and amazing new discoveries are still emerging with implications for brain health and disorders. The aim of this Research Topic is to gather recent advances in the field of glutamatergic synaptic biology.

We welcome authors to submit articles focusing on, but not limited to the following topics:

·      Interacting synaptic proteins in glutamate receptor signaling complexes

·      Glutamatergic neurotransmission and mRNA translation in physiological and pathological conditions

·      Post-translational modifications of glutamate receptors and/or their interacting partners that control their interactions, localization, trafficking and function

·      Sub-synaptic nanoscale organization of the excitatory synapse and its influence on synaptic activity

·      Crosstalk between glutamate receptors and neuromodulator receptors to control neuronal plasticity

·      Glutamatergic synapses between neurons and non-neuronal cells

·      Impact of disease-associated mutations or pathological agents on excitatory synaptic function and/or structure

·      Mechanisms of action of drugs targeting the glutamatergic synapse