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GABAergic Protection of Hippocampal Pyramidal Neurons Against Glutamate Insult: Deficit in Young Animals Compared to Adults

¹Departments of Pediatrics and ²Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico

Submitted 12 October 2005; accepted in final form 17 April 2006

Hypoxia-ischemia (HI) injury in neonatal animals leads to selective regional loss of neurons including CA1 and CA3 pyramidal neurons of the hippocampus as well as nonlethal pathologies. Glutamate-receptor over-activation and Ca²⁺ influx are involved in these neonatal changes. We examined glutamate-evoked Ca²⁺ responses in neonatal (PN 7–13) and young adult (PN 21–27) CA1 pyramidal neurons in acute slices from rats. In neonates, transient exposure to glutamate produced large Ca²⁺ increases throughout neurons, including distal dendrites (primary Ca²⁺ responses). Repeated exposures resulted in sustained Ca²⁺ increases in apical dendrites (secondary Ca²⁺ responses) that were independent of continued glutamate exposure. These responses propagated and invaded the soma, resulting in irrecoverably high Ca²⁺ elevations. In neurons from adults, identical glutamate exposure evoked primary Ca²⁺ responses only in somata and proximal apical dendrites. Repeated glutamate exposures in the adult neurons also led to secondary Ca²⁺ responses, but they arose in the peri-somatic region and then spread outward to distal apical dendrites, again without recovery. More stimuli were required to initiate secondary responses in neurons from adult versus neonates. Block of GABA_A receptors in adults caused the primary and secondary responses to revert to the spatial pattern seen in the neonates and greatly increased their vulnerability to glutamate. These findings suggest that neurodegenerative secondary Ca²⁺ events may be important determinants of susceptibility to HI injury in the developing CNS and that immature CA1 neurons may be more susceptible to excitotoxic injury due at least in part to insufficient development of GABAergic inputs to their dendrites.

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