Effects of chronic network hyperexcitability on the growth of hippocampal dendrites

Abstract

Experiments reported here were motivated by studies in both human epilepsy and animal models in which stunted dendritic arbors are observed. Our goal was to determine if chronic network hyperexcitability alters dendritic growth. Experiments were conducted in hippocampal slice cultures obtained from infant mice that express the fluorescent protein YFP in CA1 hippocampal pyramidal cells. Results showed that 4 days of GABAa receptor blockade produced a 40% decrease in basilar dendritic length. When dendritic growth was followed over this 4 day interval, dendrites in untreated slices doubled in length, however dendrites in bicuculline treated cultures failed to grow. These effects were suppressed by APV -suggesting a dependence on NMDA receptor activation. Activation of the transcription factor CREB was also decreased by chronic network hyperexcitability -pointing to possible molecular events underlying the observed suppression of growth. Taken together, our results suggest that chronic hippocampal network hyperexcitability limits dendritic growth.

Curing epilepsy: Progress and future directions

“…These microarray findings are consistent with previous results in both animal models and humans, which have suggested roles for IL1-b and COX-2 in epileptogenesis [50–54]. Other groups are evaluating changes in synaptic components, including receptor expression and distribution [55–57]. …”

“…In humans, hippocampal neuronal cell death accompanies seizures and predicts the extent of memory loss following seizures [115]. In neonates, seizures interfere with the development of hippocampal dendrites and the maturation of GABAergic and glutaminergic receptors and scaffolding proteins [55–57]. Dendritic loss and/or abnormalities of dendritic development are also seen in humans with epilepsy [116,117] as well as in Down syndrome and other forms of mental retardation [118].…”

Stabilizing dendritic structure as a novel therapeutic approach for epilepsy

“…Similar to the clinical findings, a loss of dendritic spines and varicose swelling of dendrites is frequently found in histological sections obtained from rats that had acute seizures or chronic epilepsy induced in vivo by various methods, such as convulsant drugs or electrical kindling [60][61][62][63][64][65], although rarely an increase in dendrites or spines has been reported [66][67][68]. Furthermore, spine loss and other dendritic changes can also occur with in vitro seizure models involving epileptiform bursting in brain slice-cultures [69][70][71][72]. While previous studies have utilized fixed-tissue methods to give isolated, static views of dendritic injury, recently modern microscopy methods have directly visualized seizure-related dendritic injury with time-lapse imaging in living animals in vivo [73][74][75].…”

The effects of early-life seizures on hippocampal dendrite development and later-life learning and memory

“…One simple explanation for the learning deficits could be that the seizures kill some hippocampal neurons. However, numerous investigators have shown this is not the case (Nitecka et al, 1984; Liu et al, 1999; Lee et al, 2001; Riviello et al, 2002; Nishimura et al, 2008). …”

“…When dendrites from control (no bicuculline) slice cultures were reconstructed from confocal stacks, results demonstrated (as we had hoped) a rapid growth of CA1 pyramidal cell dendrites from DIV 3-7. Basilar dendrites grew both in length and branching complexity (Nishimura et al, 2008). In contrast, after as little as 24 hours of epileptiform activity, the length and branching complexity of slices treated with bicuculline was reduced and dendrites failed to grow over the next 4 days (Nishimura et al, 2008).…”