Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability

Abstract

Glutamate is the most abundant neurotransmitter of the central nervous system, as the majority of neurons use glutamate as neurotransmitter. It is also well known that this neurotransmitter is not restricted to synaptic clefts, but found in the extrasynaptic regions as ambient glutamate. Extrasynaptic glutamate originates from spillover of synaptic release, as well as from astrocytes and microglia. Its concentration is magnitudes lower than in the synaptic cleft, but receptors responding to it have higher affinity for it. Extrasynaptic glutamate receptors can be found in neuronal somatodendritic location, on astroglia, oligodendrocytes or microglia. Activation of them leads to changes of neuronal excitability with different amplitude and kinetics. Extrasynaptic glutamate is taken up by neurons and astrocytes mostly via EAAT transporters, and astrocytes, in turn metabolize it to glutamine. Extrasynaptic glutamate is involved in several physiological phenomena of the central nervous system. It regulates neuronal excitability and synaptic strength by involving astroglia; contributing to learning and memory formation, neurosecretory and neuromodulatory mechanisms, as well as sleep homeostasis.The extrasynaptic glutamatergic system is affected in several brain pathologies related to excitotoxicity, neurodegeneration or neuroinflammation. Being present in dementias, neurodegenerative and neuropsychiatric diseases or tumor invasion in a seemingly uniform way, the system possibly provides a common component of their pathogenesis. Although parts of the system are extensively discussed by several recent reviews, in this review I attempt to summarize physiological actions of the extrasynaptic glutamate on neuronal excitability and provide a brief insight to its pathology for basic understanding of the topic.

d-glutamate and Gut Microbiota in Alzheimer’s Disease

“…Neurons uptake glutamine and convert glutamine into glutamate by the deaminase [60]. This transportation and metabolization prevents the high levels of extracellular glutamate resulting in neuron excitotoxicity [63]. However, the different anatomical distribution and transportation of D-glutamate in humans remains unclear.…”

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

“…Glutamate neurotransmission is regulated by astrocytes and microglia processes surrounding the synapse (Murugan et al, 2013). Glutamate transporters, Glt-1 and GLAST (located on astrocytes), rapidly remove glutamate from the extracellular space, restricting glutamate to the synaptic cleft (Danbolt, 2001;Pal, 2018). When spillover does occur, feedback through the metabotropic glutamate receptor 2 (mGluR2) can reduce presynaptic release of glutamate (Loane et al, 2012).…”

Interleukin-16 inhibits sodium channel function and GluA1 phosphorylation via CD4- and CD9-independent mechanisms to reduce hippocampal neuronal excitability and synaptic activity

“…It is well established that glutamate mediates its effects via both ionotropic and metabotropic glutamate receptors. However, as the role of ionotropic glutamate receptors in hippocampal astrocytes remains unclear (Pál, 2018;Rose et al, 2018), our data may indicate that IL-16 selectively modulates neuronally expressed ionotropic glutamate receptors.…”