Glutamate Degradation

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After astrocytes remove glutamate from the ECS, glutamate must be isolated and degraded. Glutamate transporters are bidirectional, so intracellular elevations of glutamate levels will lead to an electrochemical gradient-mediated release if the molecule is not destroyed. If glutamate release is unregulated glutamate accumulates in the ECS and impairs the survival of neurons. Glutamate dehydrogenase (GDH) helps degrade glutamate into a-ketoglutarate, an intermediary in the tricarboxylic acid (TCA) cycle (Coulter and Steinhauser, 2015). Superfluous glutamate release depletes the TCA cycle of intermediates and impairs ATP synthesis (Coulter and Eid, 2012). Another degradation enzyme is glutamine synthetase (GS), found predominantly in astrocytes …show more content…
In glutamatergic neurons, glutamine is converted back into glutamate and reused as a neurotransmitter. In GABAergic neurons, glutamine is first recycled back into glutamate and then further converted into GABA by GAD65 or GAD67. GABA signaling is largely responsible for inhibitory neurotransmission in the mammalian brain (Coulter and Eid, 2012). Hippocampal and thalamic inhibitory synapses are rapidly impacted when the glutamate-glutamine cycle is compromised. The predominant consequence may to be reduce GABA synthesis and release from inhibitory synapses and thus enhance network excitability. Hyperactivation in the CA1 hippocampal region is specifically evident as this area is extensively regulated by inhibitions pathways (Coulter and Steinhauser, 2015). GABA also functions as a gliotransmitter to activate high affinity GABA receptors to mediate long lasting inhibition. Release of GABA from glial cells in the cerebellum is independent of neuronal activity and works along non-vesicular processes (Yoon and Lee, 2014). Release of neuronal or glial GABA promotes inhibition by acting on type-A ionotropic GABA receptors (GABAA Rs) and type-B metabotropic GABA receptors (GABAB Rs) on the post-synaptic neuron. GABAA Rs shunt excitatory depolarization and control tonic inhibition. These receptors are constitutively targeted for degradation and insertion to fine tune inhibitory synaptic transmission. Alternations to tonic GABAA receptor-mediated activity in the hippocampus was found in TLE animal models. Postmortem studies have shown a severe decrease of extrasynaptic GABAA Rs which may be related to loss of GABAergic interneurons and a decrease in GABA availability. Loss of GABAB Rs expression has also been shown in TLE patients and animal models. GABAB Rs promote activation of Kir channels which results in sustained hyperpolarization (Bonansco and Fuenzalida, 2016). By releasing gliotransmitters,

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