Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease

Abstract

Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptors (AMPAR) are a central mediator of glutamatergic excitatory synaptic transmission, yet they are also expressed in a wide range of glial cells where they influence a variety of important cellular functions. AMPAR enable glial cells to sense the activity of neighbouring axons and synapses, and as such many aspects of glial cell development and function are influenced by the activity of neural circuits. However, these AMPAR also render glia sensitive to elevations of the extracellular concentration of glutamate, which are associated with a broad range of pathological conditions. Excessive activation of AMPAR under these conditions may induce excitotoxic injury in glial cells, and trigger pathophysiological responses threatening other neural cells and amplifying ongoing disease processes. The aim of this review is to gather information on AMPAR function from across the broad diversity of glial cells, identify their contribution to pathophysiological processes, and highlight new areas of research whose progress may increase our understanding of nervous system dysfunction and disease.

Ionotropic Glutamate Receptors in Epilepsy: A Review Focusing on AMPA and NMDA Receptors

“…RAB39B dysfunction causes impaired trafficking of GluA2/GluA3 to the Golgi compartment, resulting in increased levels of non-GluA2-containing calcium-permeable forms of the AMPA receptor. AMPA receptors lacking the GluA2 subunit are predominantly observed in young animals or after an event of plasticity-inducing neuronal activity [7,[33][34][35], while mouse GRIA2 knockouts, lacking GluA2, exhibit a greater magnitude of long-term potentiation and non-saturated long-term potentiation [111]. This transgenic animal observation might suggest that the GluA2-lacking brain may enhance its activity by repetitive, strong excitation.…”

“…The GluA2 subunit is the determinant of calcium permeability; GluA2-containing calcium-impermeable AMPA receptors are mainly expressed in excitatory projection neurons [19], whereas calcium-permeable AMPA receptors (lacking the GluA2 subunit) are mainly expressed in inhibitory interneurons [32,33]. Expression of calcium-permeable AMPA receptors has also been observed at excitatory neuronal synapses under conditions of synaptic plasticity, including physiological plasticity and after pathological insult [7,34,35]. AMPA receptor turnover at synapses is considered continuous and fast.…”

“…Cortical pyramidal neurons possess approximately 30,000 synapses, of which 95% are excitatory synapses [3], indicating that glutamate is the principal excitatory neurotransmitter in the brain, and also that GABAergic inhibition influences neuronal activity in an efficient manner [4]. Recently, it has been demonstrated that glutamate is also utilized as a gliotransmitter, released from glial vesicles and channels, with evidence suggesting that glutamate released from glial cells modulates synaptic efficiency [5,6] and controls the release of various biological molecules, including cytokines [7]. Therefore, it is possible that glutamate may contribute to various physiological/pathological conditions.…”

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

“…Glutamatergic signaling through glutamate receptors forms a major component of excitatory synaptic transmission in the CNS. However, glutamate release in the CNS is not exclusive to synaptic terminals but also arises from unmyelinated axons and glial cells under both physiological and pathophysiological conditions (Ceprian and Fulton, 2019). Glial cells express both types of glutamate receptors-ionotropic (NMDA, AMPA, and kainate) and metabotropic in gray and white matter.…”

“…Glial cells express both types of glutamate receptors-ionotropic (NMDA, AMPA, and kainate) and metabotropic in gray and white matter. For reviews, see D' Antoni et al (2008), Dzamba et al (2013), Ceprian and Fulton (2019) and Fern and Matute (2019).…”