Epileptogenesis Up-Regulates Metabotropic Glutamate Receptor Activation of Sodium-Calcium Exchange Current in the Amygdala

Abstract

Postsynaptic metabotropic glutamate (mGlu) receptor-activated inward current mediated by Na(+)-Ca(2+) exchange was compared in basolateral amygdala (BLA) neurons from brain slices of control (naïve and sham-operated) and amygdala-kindled rats. In control neurons, the mGlu agonist, quisqualate (QUIS; 1-100 microM), evoked an inward current not associated with a significant change in membrane slope conductance, measured from current-voltage relationships between -110 and -60 mV, consistent with activation of the Na(+)-Ca(2+) exchanger. Application of the group I selective mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine [(S)-DHPG; 10-1000 microM] or the endogenous agonist, glutamate (10-1000 microM), elicited the exchange current. QUIS was more potent than either (S)-DHPG or glutamate (apparent EC(50) = 19 microM, 57 microM, and 0.6 mM, respectively) in activating the Na(+)-Ca(2+) exchange current. The selective mGlu5 agonist, (R, S)-2-chloro-5-hydroxyphenylglycine [(R,S)-CHPG; apparent EC(50) = 2. 6 mM] also induced the exchange current. The maximum response to (R, S)-DHPG was about half of that of the other agonists suggesting partial agonist action. Concentration-response relationships of agonist-evoked inward currents were compared in control neurons and in neurons from kindled animals. The maximum value for the concentration-response relationship of the partial agonist (S)-DHPG- (but not the full agonist- [QUIS or (R,S)-CHPG]) induced inward current was shifted upward suggesting enhanced efficacy of this agonist in kindled neurons. Altogether, these data are consistent with a kindling-induced up-regulation of a group I mGlu-, possibly mGlu5-, mediated responses coupled to Na(+)-Ca(2+) exchange in BLA neurons.

Alteration in NCX-3 immunoreactivity within the gerbil hippocampus following spontaneous seizures

“…Because some investigators have suggested that seizure-induced alterations of intracellular Ca 2+ concentration are accompanied by changes in the expression and/or function of calcium-extrusion proteins (15,21,22), our findings indicate that down-regulation of NCX-3 expression may be closely related to spontaneous seizure activity in gerbils. Indeed, persistent alterations in the intracellular Ca 2+ concentration and calcium homeostasis arise during epileptogenesis and associated with the epileptic phenotype (10,15,17).…”

“…Therefore, Mongolian gerbils allow an epileptic and non-epileptic animals to be directly compared, which allows differences in brain anatomy and electrophysiologic properties correlated with seizure behavior to be identified (17)(18)(19). In addition, the seizure activity in this animal model has been linked to the functional alteration of various ion channels/transporters (19)(20)(21)(22). However, differences in the expression of NCX-3 immunoreactivity in the epileptic gerbil hippocampus remain to be clarified, specifically, it is not known whether or not the altered expression of NCX-3 correlates with seizure activity in the Mongolian gerbil.…”

Molecular Targets for Antiepileptic Drug Development

“…In the kindling model of epilepsy, there is upregulation of group I receptors that can be demonstrated by biochemical or electrophysiological functional assays. 290,291 There is also upregulation of mGluR5 in the hippocampus of patients with complex partial seizures. 292 In contrast, downregulation of hippocampal group II mGluRs was seen in chronically epileptic rats that experienced pilocarpineinduced status epilepticus.…”

Synaptic Plasticity in the Amygdala in a Model of Arthritic Pain: Differential Roles of Metabotropic Glutamate Receptors 1 and 5

“…The role of mGluRs in the brain, however, in prolonged, and chronic pain states are for the most part unknown. Accumulating evidence suggests a role of mGluRs in the amygdala in synaptic plasticity associated with behavioral modifications (Holmes et al, 1996;Neugebauer et al, 1997aNeugebauer et al, ,b, 2000Masugi et al, 1999;Keele et al, 2000;Lin et al, 2000). Thus, it is conceivable that mGluRs also contribute to pain-related synaptic plasticity in the amygdala.…”