The excitatory and excitotoxic actions of the endogenous excitatory amino acid (EAA) neurotransmitter, glutamate, are mediated by activation of three common subtypes of EAA receptors: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/quisqualate and kainate receptors. EAA neurotransmitter systems play a number of physiological roles in the regulation and organization of neural systems during development. However, excessive activation of this neurotransmitter system is also implicated in the pathophysiology of several forms of acute and chronic brain injury. In this study, the susceptibility of the developing rat brain to AMPA/quisqualate receptor mediated injury was examined at eight postnatal ages (1–90 days). The receptor agonists, AMPA (25 nmol) or quisqualate (100 nmol), were stereotaxically microinjected unilaterally into the anterior striatum. The severity of resulting brain injury was assessed 5 days later by comparison of reductions in regional cortical and striatal cross-sectional areas. Microinjection of AMPA (25 nmol) produced widespread unilateral forebrain injury in the intermediate postnatal period (days 5–28). The severity of injury resulting from microinjection of a fixed dose of AMPA (25 nmol) transiently exceeded the severity of injury in adults between PND 5–28 with peak sensitivity occurring near PND 10. At PND 1, microinjection of AMPA produced a 24.5 ± 1.7% reduction in striatal cross-sectional area, which is similar to the response observed in adult animals, and the lesion was confined to the injection site. Susceptibility to AMPA toxicity increased 2-fold from PND 1 to PND 5. At PND 10, the age of maximal sensitivity, the excitotoxic reaction,to AMPA extended throughout the entire cerebral hemisphere and the mean striatal cross-sectional area was reduced by 81.7 ± 3.9%. With advancing postnatal age, the severity of injury progressively diminished and the lesion became confined to the injection site. The developmental pattern of sensitivity to AMPA toxicity in other brain regions differed although peak sensitivity consistently occurred near PND 10. Microinjection of quisqualate produced a developmental pattern of striatal susceptibility similar to AMPA although quisqualate was a considerable less potent neurotoxin. In additional experiments, the in vivo pharmacology of AMPA and quisqualate mediated brain injury was evaluated in a PND 7 rat model in order to determine the neurotoxic characteristics and specificity of these agonists in vivo. The severity of brain injury was assessed 5 days after intrastriatal excitotoxin injection by comparison of cerebral hemisphere weights. Co-intrastriatal injection of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a competitive ionotropic type quisqualate receptor antagonist, with either AMPA (10 nmol) or quisqualate (100 nmol) attenuated toxicity in a dose-dependent manner with 70% maximal reduction (20 nmol CNQX). However, CNQX (20 nmol) was much less effective against toxicity induced by 10 nmol NMDA (30% reduction). Co-administration of the NMDA receptor antagonist MK-801 (1 mg/kg, i.p., a dose which completely blocks NMDA toxicity in this model) reduced the severity of AMPA or quisqualate induced injury by less than 30%. The anticonvulsants, diazepam and Phenytoin, were ineffective against AMPA toxicity and moderately effective against quisqualate toxicity. These findings indicate that AMPA/quisqualate toxicity in vivo is mediated predominantly by selective activation of ionotropic type quisqualate receptors. These findings support previous evidence indicating that EAA neurotransmitter systems undergo marked changes during postnatal development and suggest that there is a transient period during development in which particular populations of neurons are hypersensitive to AMPA/quisqualate receptor mediated injury.
All Science Journal Classification (ASJC) codes
- General Neuroscience
- Molecular Biology
- Clinical Neurology
- Developmental Biology