Abstract
BackgroundExcitotoxicity occurs in a number of pathogenic states including stroke and epilepsy. The adaptations of neuronal circuits in response to such insults may be expected to play an underlying role in pathogenesis. Synchronous neuronal firing can be induced in isolated hippocampal slices and involves all regions of this structure, thereby providing a measure of circuit activity. The effect of an excitotoxic insult (kainic acid, KA) on Mg2+-free-induced synchronized neuronal firing was tested in organotypic hippocampal culture by measuring extracellular field activity in CA1 and CA3.ResultsWithin 24 hrs of the insult regional specific changes in neuronal firing patterns were evident as: (i) a dramatic reduction in the ability of CA3 to generate firing; and (ii) a contrasting increase in the frequency and duration of synchronized neuronal firing events in CA1. Two distinct processes underlie the increased propensity of CA1 to generate synchronized burst firing; a lack of ability of the CA3 region to 'pace' CA1 resulting in an increased frequency of synchronized events; and a change in the 'intrinsic' properties limited to the CA1 region, which is responsible for increased event duration. Neuronal quantification using NeuN immunoflurescent staining and stereological confocal microscopy revealed no significant cell loss in hippocampal sub regions, suggesting that changes in the properties of neurons within this region were responsible for the KA-mediated excitability changes.ConclusionThese results provide novel insight into adaptation of hippocampal circuits following excitotoxic injury. KA-mediated disruption of the interplay between CA3 and CA1 clearly increases the propensity to synchronized firing in CA1.
Highlights
Excitotoxicity occurs in a number of pathogenic states including stroke and epilepsy
Organotypic hippocampal slice cultures exhibit synchronous bursts led by CA3 Synchronous discharges can be observed in Mg2+-free artificial cerebrospinal fluid (ACSF) in organotypic hippocampal slice cultures [24]
After a short delay Mg2+-free ACSF induces a burst of firing in both regions that settles into prolonged rhythmic and synchronized events. (B) Expanded region of the trace from the region indicated by asterix. (C) Further time scale expansion reveals that CA3 firing precedes activity in CA1 suggesting that under normal conditions synchronized events are paced from the CA3 region
Summary
Excitotoxicity occurs in a number of pathogenic states including stroke and epilepsy. Synchronous neuronal firing can be induced in isolated hippocampal slices and involves all regions of this structure, thereby providing a measure of circuit activity. The effect of an excitotoxic insult (kainic acid, KA) on Mg2+-free-induced synchronized neuronal firing was tested in organotypic hippocampal culture by measuring extracellular field activity in CA1 and CA3. The ultimate pathogenic outcome of an excitotoxic insult is likely to be reflected in changes in neuronal network activity. Heterogeneous changes in subtype and extent of HCN mRNA are evident in in vivo [3] and in vitro [27] KA models. These changes occur within 24 hours and are likely to impact on network activity in a regional specific manner. Synchronized network firing is an encompassing parameter that integrates these various plastic changes
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