Excitotoxic neonatal damage induced by monosodium glutamate reduces several GABAergic markers in the cerebral cortex and hippocampus in adulthood

Abstract

Monosodium glutamate (MSG) administered to neonatal rats during the first week of life induces a neurodegenerative process, which is represented by several neurochemical alterations of surviving neurons in the brain, where signalling mediated by GABA is essential for excitation threshold maintenance. GABA-positive cells, [(3)H]-GABA uptake, expression of mRNA for GABA transporters GAT-1 and GAT-3, and expression of mRNA and protein for two main GABA synthesizing enzymes, GAD(65) and GAD(67), were measured at postnatal day 60, after MSG neonatal treatment in two critical cerebral regions, cerebral cortex and hippocampus. GABA-positive cells, [(3)H]-GABA uptake, and mRNA for GAT-1, were significantly diminished in both cerebral regions. In the cerebral cortex, MSG neonatal treatment also decreased the mRNA for GAD(67) and protein for GAD(65) without significant changes in its corresponding protein and mRNA, respectively. Moreover in the hippocampus, mRNA and protein for GAD(65) were increased, whilst GAD(67) protein was elevated without significant changes in its mRNA. Clearly these results confirm the GABA cells loss after MSG neonatal treatment in both cerebral regions. As most of the GABAergic markers measured were reduced in the cerebral cortex, this region seems to be more sensitive than hippocampus, where interesting compensatory changes over GAD(65) and GAD(67) proteins were observed. However, it is possible that others neurotransmission systems are also compensating the GABA-positive cells loss in the cerebral cortex, and that elevations in two main forms of GAD in the hippocampus are not sufficient to maintain the neural excitation threshold for this region.

KB-R7943 reduces 4-aminopyridine-induced epileptiform activity in adult rats after neuronal damage induced by neonatal monosodium glutamate treatment

“…Evidence on the roles of NCX1 is contradictory, as NCX1 knock-out mice are resistant to seizures induced by pentylenetetrazole [74], but NCX1 downregulation has been related to epileptogenesis in a kindling model [69]. Here, even though MSG-treated rats show an augmented expression of NCX3 and NCX1, they are more susceptible to seizures induced by 4-AP [44], probably because the changes in the expression of NCXs are accompanied by a very broad and complex set of modifications [18, 25], including reductions in GABAergic inhibitory neurotransmission [14, 15]. Then changes in NCXs described above are only a part of the mechanisms implicated in the process by which MSG-treated rats are more susceptible to seizures induced by 4-AP [44].…”

“…In contrast, when KB-R7943 was applied in combination with 4-AP, it is possible that reverse mode blocking happen, since prolonged neural depolarization induces inversion of NCXs [65, 67, 75]. In addition, if we take in count that in MSG-treated rats: 1) neural inhibition mediated by GABA is reduced [14, 15, 44] and 2) NCX1 and NCX3 are overexpressed; then it is possible that the NCXs inversion may be reached sooner than in control rats; however more studies are necessary to clarify these statements.…”

“…Monosodium glutamate (MSG) is probably the broad-spectrum glutamate analogue most used to study excitotoxic neuronal damage [7, 8]. Neonate animals are more susceptible to MSG toxic effects, and repeated systemic administration of MSG at neonatal age produces neuronal death in the short term [9, 10] and several degenerative changes in the long term [11–14]. The expression levels and functionality of numerous enzymes [15, 16], receptors [9, 10, 17, 18] and transporters [14, 19] are modified by neonatal MSG treatment.…”

“…Neonate animals are more susceptible to MSG toxic effects, and repeated systemic administration of MSG at neonatal age produces neuronal death in the short term [9, 10] and several degenerative changes in the long term [11–14]. The expression levels and functionality of numerous enzymes [15, 16], receptors [9, 10, 17, 18] and transporters [14, 19] are modified by neonatal MSG treatment. Recently, a significant increase in the expression level of mRNA encoding the sodium/calcium (Na + /Ca 2+ ) exchanger type 3 (NCX3) was reported in the hippocampus (Hp) twenty hours after cessation of treatment [19], but it is unknown if neonatal MSG treatment has any long-term effects on this exchanger.…”

“…Because neonatal MSG treatment modifies several GABAergic markers and reduces GABA-positive cell density in the Hp of adult male rats [14, 15], seizure susceptibility was thought to be altered by MSG treatment. Therefore, preliminary results published by our group showed that neonatal MSG treatment increases the susceptibility to seizures induced by 4-aminopyridine (4-AP), reaching more severe convulsive signs with lower doses than in intact animals [44].…”