• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • br Materials and Methods br Results br Discussion A model


    Materials and Methods
    Discussion A model of seizure and excitotoxicity induced by neonatal MSG administration was described recently (19) in which extracellular glutamate increased after the first and second MSG administrations were observed, the greatest increase seen following the first administration in hippocampal region. Indeed, these increases are associated with convulsive behavior and epileptiform discharges. These findings suggest an important effect of early glutamate exposure on the glutamatergic system. It has been shown that MSG induced molecular and morphological changes at either PD 14 or 60 26, 29, 30, 31. However, this is the first study to examine the effect of MSG administration on the expression of the primary glutamate and GABA hippocampal transporters at two different ages, PD 14 and 60. Our results show that EAAT-3 is found around the soma of granular and pyramidal Go 6976 in the DG and CA1, respectively, as well as in the dendrites and neuropil of both regions in control and experimental animals at the ages studied. These observations are in agreement with the distribution of this protein in the hippocampus of intact adult rats 6, 7, 20, 21, 22. At 60 PD, the number of granular cells co-labelled with EAAT-3/Neun in the DG increased significantly following MSG administration when compared to the controls, whereas no significant effect of MSG administration was observed at 14 PD. No alterations in EAAT-3 expression were observed in the CA1 region of the hippocampus. These findings suggest that EAAT-3 transporters in granular cells are more susceptible to early glutamate exposure, as observed elsewhere in GABAergic terminals. The inhibitory terminals that express EAAT-3 are sensitive and rapid detectors of this extracellular transmitter, making pre-synaptic transmitter uptake a crucial element in homeostatic plasticity of hippocampal networks (32). In addition, the increase in EAAT-3 expression in this study is consistent with the increased EAAT-3 expression in the DG of early-seizing adult animals in other seizure models, as well as in TLE patients 33, 34. This selective long-term alteration in EAAT-3 expression could reflect an important compensatory mechanism to increase the clearance of glutamate from the synaptic cleft in response to the cellular damage caused by early glutamate exposure in this region. This hypothesis is supported by evidence of a central role for neuronal EAAT-3 transporters in glutamate clearance at synaptic sites (35). Alternatively, increased EAAT-3 protein expression in granular cells could augment GABA metabolism, thereby enhancing inhibitory transmission in these neurons, which is in agreement with reports of seizure-induced GABAergic fast synaptic inhibition in the mossy fibers of the DG to CA3 system (36). Moreover, there is evidence that granule cells contain GAD/GABA and that seizures transiently upregulate its synthesis 37, 38. Furthermore, this alternative hypothesis coincides with recent evidence that the EAAT-3 transporter in presynaptic inhibitory terminals participates in the rapid adaptation of these terminals to changes in local network activity by recovering the vesicular transmitter content and GABA release. This compensatory or protective mechanism allows extracellular glutamate to reinforce the inhibitory synapses in order to stabilize the excitation-inhibition equilibrium under seizure conditions 39, 40. In addition, it is possible that the long-lasting increases in EAAT-3 expression observed in granular cells at PD 60 may represent a compensatory and, more precisely, a protective response to the high extracellular glutamate levels induced by the early effect of MSG. This effect may reinforce inhibitory synapses as a consequence of the stationary GAT-1 expression in the granular and pyramidal layer of the hippocampus at the different ages studied. In both control and experimental rats, GAT-1 expression was detected around the soma of granular cells and in the neuropil of the DG, as well as in the soma and dendrites of pyramidal cells in the CA1, at both ages studied. These observations are in agreement with the distribution of GAT-1 previously described in hippocampal neurons of adult rats (14). No changes in GAT-1 protein expression were observed in the DG or CA1 at either PD 14 or 60, in contrast to previous reports of decreased hippocampal GAT-1 mRNA at PD 60 following MSG administration (27). These conflicting findings may reflect differences in the levels of mRNA and protein expression or, alternatively, they may indicate that the principal neurotransmitter system affected in this model of seizure and excitotoxicity is glutamate.