ABSTRACT
"Brain tolerance"--a phenomenon in which a subtoxic challenge confers resistance to subsequent brain injuries--provides an ideal opportunity for investigating endogenous neuroprotective mechanisms. We investigated the potential role of the polysialylated (PSA) form of neural cell adhesion molecule (NCAM), which is thought to play a key role in plasticity. In a model where prior exposure to heat shock protects against kainate-induced cell damage in the hippocampus, we show that hyperthermia upregulates PSA-NCAM expression for at least 1 week, without affecting neurogenesis. Pharmacological manipulation of heat shock protein (HSP) expression demonstrates a tight positive link between HSP70 and PSA-NCAM. Finally, the presence of PSA was functionally linked to brain tolerance, as protection against kainate-induced cell death by heat shock pre-exposure was abolished in the absence of NCAM polysialylation. The upregulation of PSA-NCAM by hyperthermia may have a significant impact on hippocampal plasticity, permitting induction of the complex molecular cascade responsible for neuroprotection.
Subject(s)
Brain Damage, Chronic/metabolism , Cytoprotection/physiology , Fever/metabolism , Heat-Shock Response/physiology , Hippocampus/metabolism , Neural Cell Adhesion Molecule L1/metabolism , Sialic Acids/metabolism , Animals , Body Temperature/physiology , Brain Damage, Chronic/physiopathology , Cell Death/drug effects , Cell Death/physiology , Fever/physiopathology , HSP70 Heat-Shock Proteins/metabolism , Hippocampus/physiopathology , Male , Nerve Degeneration/chemically induced , Nerve Degeneration/metabolism , Nerve Degeneration/physiopathology , Neurons/metabolism , Neurotoxins/toxicity , Rats , Rats, Wistar , Up-Regulation/physiologyABSTRACT
In adult mice, intrahippocampal administration of kainic acid induces a structural modification of the granule cell layer reminiscent of granule cell dispersion (GCD) seen in humans with temporal lobe epilepsy. We tested that GCD might be involved in the patterns of granule cell responses to perforant path stimulation by recording field potentials in vivo after kainic acid-induced status epilepticus until the phase of chronic seizure activity in presence of GCD or after its alteration by K252a co-treatment, an inhibitor of tyrosine kinase activities. Stimulation triggered bursts of multiple population spikes, the number of which progressively increased with time whereas their amplitude decreased in parallel with the progressive decrease in granule cell density. The population spike threshold was reached for a lower excitatory synaptic drive than in controls, as assessed by the initial slope of the field excitatory post-synaptic potential. This indicates that, for identical synaptic responses, granule cells were closer to the firing threshold. Fast inhibition, assessed by paired pulse stimulation, was compromised immediately after the initial status epilepticus, consistent with the rapid loss of most hilar cells. Neither the epileptic course nor the epileptiform responses of the granule cells were modified and manipulation by alteration following GCD manipulation while granule cell neuropeptide-Y immunostaining was substantially decreased. In this mouse model of TLE, granule cells display a progressive increase in epileptiform responses to afferent input until the occurrence of spontaneous seizures. The population spike amplitude decreases in parallel with GCD while the granule cell excitability is enhanced. Consequently, data from field potentials in epilepsy experiments should be interpreted with care, taking into account the possible variations in the neuronal density in the recorded area.
Subject(s)
Epilepsy/physiopathology , Hippocampus/cytology , Neurons/physiology , Perforant Pathway/physiopathology , Action Potentials/drug effects , Action Potentials/physiology , Action Potentials/radiation effects , Animals , Behavior, Animal/drug effects , Carbazoles/pharmacology , Cell Count/methods , Disease Models, Animal , Dose-Response Relationship, Radiation , Drug Interactions , Electric Stimulation/methods , Enzyme Inhibitors/pharmacology , Epilepsy/chemically induced , Epilepsy/pathology , Hippocampus/pathology , Immunohistochemistry/methods , Indole Alkaloids , Kainic Acid , Mice , Neurons/drug effects , Neurons/radiation effects , Neuropeptide Y/metabolism , Perforant Pathway/drug effects , Perforant Pathway/radiation effects , Staining and Labeling/methods , Time FactorsABSTRACT
A bilamination involving the whole dentate stratum granulosum associated with a hippocampal sclerosis is reported. This morphological abnormality could be an unusual aspect of granule cell dispersion, plastic change induced by an early post-natal injury, or the the result from a neuronal migration disorder during the embryonic period. Whatever its origin, this bilamination is an abnormality of the hippocampal development which continues during the first years of life.
