Rat intra-hippocampal NMDA infusion induces cell-specific damage and changes in expression of NMDA and GABAA receptor subunits

Abstract

Excessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABAA 5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABAA receptors. Highlights:1. The infusion of NMDA induced degeneration of hippocampal principal cells. 2. Neurodegeneration was accompanied with progressive and severe neuroinflammation. 3. The lesion did not induce loss of GABAergic interneurons. 4. GluN1 and GluN2B subunits of NMDA receptor were upregulated at early time points.5. GABA A receptor α5 subunit was downregulated at 30 days after the lesion. ABSTRACTExcessive stimulation of NMDA receptors with glutamate or other potent agonists such as NMDA leads to excitotoxicity and neural injury. In this study, we aimed to provide insight into an animal model of brain excitotoxic damage; single unilateral infusion of NMDA at mild dose into the hippocampal formation. NMDA infusion induced chronic, focal neurodegeneration in the proximity of the injection site. The lesion was accompanied by severe and progressive neuroinflammation and affected preferentially principal neurons while sparing GABAergic interneurons. Furthermore, the unilateral lesion did not cause significant impairment of spatial learning abilities. Finally, GluN1 and GluN2B subunits of NMDA receptor were significantly upregulated up to 3 days after the NMDA infusion, while GABA A α5 subunit was downregulated at 30 days after the lesion. Taken together, a single infusion of NMDA into the hippocampal formation represents an animal model of excitotoxicity-induced chronic neurodegeneration of principal neurons accompanied by severe neuroinflammation and subunit specific changes in NMDA and GABA A receptors.

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity

“…The excitotoxic effect of QA is influenced by NMDAR subunit composition5253 and modulated by metabotropic glutamate receptors54. QA shares with NMDA its property to damage preferentially pyramidal neurons, while sparing other neuron types55. Notably, QA has been shown to produce oxidative damage, independent of its activity at the NMDAR, by forming complexes with Fe 2+ that mediate the generation of reactive oxygen species (ROS)5657.…”

Aberrant expression of PAR bZIP transcription factors is associated with epileptogenesis, focus on hepatic leukemia factor

“…To explore this possibility, we injected either N-methyl-D-aspartic acid (NMDA) or bicuculline into the right dorsal hippocampus. Hippocampal injection of NMDA stimulates ionotropic NMDA receptors, induces acute excitotoxicity and status epilepticus; however, unlike KA-induced status epilepticus, does not cause an early loss of hippocampal interneurons 22,36 . Bicuculline is a competitive antagonist of GABA A receptors and it is known to produce seizures in the absence of neurodegenerative events 37 .…”

“…After 14 days of expression, animals were sacrificed, and their brain processed for the gene expression and fluorescent microscopy analyses. Histology and immunohistochemistry were performed as described in our previous work 22,23 . Brain sections were stained with the following antibodies: GFAP (DAKO Schweiz, Z334, 1:20000), Iba-1 (Wako, 019-19741, 1:3000) and NeuN (Chemicon, MAB377, 1:1000).…”

Protective effect of Achyranthes bidentata polypeptides on NMDA-mediated injury is developmentally regulated via modulating NR2A and NR2B differentially

“…NMDA receptors are a subtype of ionic glutamate receptors, and are characterized of high permeability to calcium ions (18). Considerable literature has demonstrated that calcium influx via NMDA receptor is the key step in glutamate-induced excitotoxicity.…”

“…Receptors for NMDA that are ligand-gated ion channels play a critical role in NMDA-induced neurotoxicity (17). The activation of NMDA receptors is identified by the influx of Na + , Cl − , Ca 2+ ions, which are examined by whole-cell patch clamp recording in cultured hippocampal neurons (18). The NMDA-elicited currents were measured in Mg 2+free solution containing Ca 2+ (2 mM), with 2-minute bath perfusion after NMDA current was recorded.…”