Pathophysiology of Extrasynaptic Glutamatergic Signaling: Excitotoxicity and Beyond

Glutamate is known as the most abundant excitatory neurotransmitter in the central nervous system. However, the actions of this neurotransmitter are not restricted to the synaptic cleft, as glutamate appears in the extracellular space at a lower concentration and activates extrasynaptic glutamate receptors of neurons and non-neuronal elements.

Extrasynaptic glutamate is involved in multiple physiological processes of the central nervous system; as it regulates neuronal excitability and synaptic strength, contributes to sleep homeostasis, learning, as well as to neurosecretory and neuromodulatory mechanisms.
Extrasynaptic glutamatergic signaling is involved in pathophysiological changes of brain homeostasis, compensating or worsening the progress of several neurological and neuropsychiatric diseases. Extrasynaptic glutamate is related to excitotoxicity, neurodegeneration or neuroinflammation, contributes to neurodegenerative and neuropsychiatric diseases or tumor invasion with similar mechanisms, and possibly serves as an overlapping component of several pathogenetic processes. Disturbances of extrasynaptic glutamatergic signaling might form a common pathway of excitotoxicity, degeneration of neuronal and glial elements, as well as neuroinflammatory processes. Understanding pathologies related to extrasynaptic glutamatergic disturbances might contribute to discoveries of novel therapeutic approaches slowing the progress of various neurological diseases.

In this Research Topic, we encourage the submission of studies investigating the pathophysiology of extrasynaptic glutamate from receptor level to clinical findings. Submissions can cover findings with different methods including molecular biology, in vitro and in vivo recording from animal models, studies from human samples, as well as clinical studies. Manuscripts investigating overlaps in pathogenesis or symptoms of neurological/neuropsychiatric diseases, description of novel methods or animal models of detecting ambient glutamate or excitotoxicity-related diseases or involvement of astrocyte/microglia-neuron interactions in excitotoxicity-related changes of the central nervous system are also encouraged. Review papers summarizing novel findings of any aspects of glutamate-induced excitotoxicity or its relationship with neuroinflammatory processes are also considered.