Journal
JOURNAL OF NEUROCHEMISTRY
Volume 127, Issue 4, Pages 520-530Publisher
WILEY
DOI: 10.1111/jnc.12403
Keywords
chemosensor; eIF2; GCN2; indispensable amino acid; seizure; threonine
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Funding
- National Institutes of Health [NS043210, NS03296]
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The anterior piriform cortex (APC) is activated by, and is the brain area most sensitive to, essential (indispensable) amino acid (IAA) deficiency. The APC is required for the rapid (20min) behavioral rejection of IAA deficient diets and increased foraging, both crucial adaptive functions supporting IAA homeostasis in omnivores. The biochemical mechanisms signaling IAA deficiency in the APC block initiation of translation in protein synthesis via uncharged tRNA and the general amino acid control kinase, general control nonderepressing kinase 2. Yet, how inhibition of protein synthesis activates the APC is unknown. The neuronal K+Cl- cotransporter, neural potassium chloride co-transporter (KCC2), and GABA(A) receptors are essential inhibitory elements in the APC with short plasmalemmal half-lives that maintain control in this highly excitable circuitry. After a single IAA deficient meal both proteins were reduced (vs. basal diet controls) in western blots of APC (but not neocortex or cerebellum) and in immunohistochemistry of APC. Furthermore, electrophysiological analyses support loss of inhibitory elements such as the GABA(A) receptor in this model. As the crucial inhibitory function of the GABA(A) receptor depends on KCC2 and the Cl- transmembrane gradient it establishes, these results suggest that loss of such inhibitory elements contributes to disinhibition of the APC in IAA deficiency.
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