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Effects of essential amino acid deficiency: down‐regulation of KCC 2 and the GABA A receptor; disinhibition in the anterior piriform cortex
Author(s) -
Sharp James W.,
RossInta Catherine M.,
Baccelli Irène,
Payne John A.,
Rudell John B.,
Gietzen Dorothy W.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12403
Subject(s) - inhibitory postsynaptic potential , piriform cortex , cotransporter , biology , microbiology and biotechnology , biochemistry , endocrinology , chemistry , medicine , hippocampus , organic chemistry , sodium
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 (20 min) 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.The circuitry of the anterior piriform cortex (APC) is finely balanced between excitatory (glutamate, +) and inhibitory (GABA, −) transmission. GABA A receptors use Cl − , requiring the neural potassium chloride co‐transporter (KCC2). Both are rapidly turning‐over proteins, dependent on protein synthesis for repletion. In IAA (indispensable amino acid) deficiency, within 20 min, blockade of protein synthesis prevents restoration of these inhibitors; they are diminished; disinhibition ensues. GCN2 = general control non‐derepressing kinase 2, eIF2α = α‐subunit of the eukaryotic initiation factor 2.