Selective reductions in subpopulations of GABAergic neurons in a developmental rat model of epilepsy

Gill, Daphne A.; Ramsay, Sarah L.; Tasker, R. Andrew

doi:10.1016/j.brainres.2010.03.054

Cited by 36 publications

(24 citation statements)

References 46 publications

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“…Combined with previously published work by both us [17,18,23,26,27] and others [19,20], these data further characterize the neonatal domoate rat model as a model of epileptogenesis: in contrast to existing rat models of epilepsy that rely on acute induction of convulsive seizures. Development of predictive diagnostics and targeted therapies to prevent seizure onset in patients that are presymptomatic requires a better understanding of the pathological changes that occur during epileptogenesis.…”

Section: Expert Recommendationssupporting

confidence: 58%

“…Administration of low doses of DOM in neonatal rats does not produce overt toxicity or status epilepticus but results in permanent alterations in adult rat behavior that manifest as changes in cognition [17][18][19], attentional processing [20][21][22], anxiety [18,23], seizure threshold [24], and sleep patterns [25] that are consistent with the development of temporal lobe epilepsy (TLE). Moreover, these changes in behavior have been shown to correlate with neuropathological changes in the hippocampal formation such as mossy fiber sprouting (MFS) [17,26] and selective loss of parvalbumin-positive GABAergic interneurons [27] that are also present in both animal models of TLE produced by kainic acid [13,28] as well as human TLE patients [29]. Collectively, these multiple reports have led us to propose that low dose neonatal DOM initiates a slowly developing epileptogenic process that creates an animal model for studying the development of epilepsy and the identification of presymptomatic biomarkers of epileptogenesis (for review, see [30][31][32]).…”

Section: Introductionmentioning

confidence: 99%

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Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

et al. 2017

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Epilepsies affect about 4% of the population and are frequently characterized by a prolonged Bsilent^period before the onset of spontaneous seizures. Most current animal models of epilepsy either involve acute seizure induction or kindling protocols that induce repetitive seizures. We have developed a rat model of epilepsy that is characterized by a slowly progressing series of behavioral abnormalities prior to the onset of behavioral seizures. In the current study, we further describe an accompanying progression of cytoarchitectural changes in the hippocampal formation. Groups of male and female SD rats received serial injections of a low dose of domoic acid (0.020 mg/kg) (or vehicle) throughout the second week of life. Postmortem hippocampal tissue was obtained on postnatal days 29, 64, and 90 and processed for glial fibrillary acidic protein (GFAP), NeuN, and calbindin expression. The data revealed no significant changes on postnatal day (PND) 29 but a significant increase in hilar NeuN-positive cells in some regions on PND 64 and 90 that were identified as ectopic granule cells. Further, an increase in GFAP positive cell counts and evidence of reactive astrogliosis was found on PND 90 but not at earlier time points. We conclude that changes in cellular expression, possibly due to on-going non-convulsive seizures, develop slowly in this model and may contribute to progressive brain dysfunction that culminates in a seizure-prone phenotype.

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Section: Expert Recommendationssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

et al. 2017

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“…Imbalance of excitation and inhibition contributes to aberrant network activity (Yizhar et al, 2011) as well as epileptiform hyperexcitability (Gutnick et al, 1982). Loss of interneurons has been implicated as a potential contributor to hyperexcitability in a developmental epilepsy model (Gill et al, 2010) and in the irradiation model of cortical dysplasia (Xiang et al, 2006; Zhou et al, 2009). There is also evidence of dysfunctional inhibition in human cortical dysplasia (André et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

HCN Channel Modulation of Synaptic Integration in GABAergic Interneurons in Malformed Rat Neocortex

Albertson

Bohannon

Hablitz

2017

Front. Cell. Neurosci.

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Cortical malformations are often associated with pharmaco-resistant epilepsy. Alterations in hyperpolarization-activated, cyclic nucleotide-gated, non-specific cation (HCN) channels have been shown to contribute to malformation associated hyperexcitability. We have recently demonstrated that expression of HCN channels and Ih current amplitudes are reduced in layer (L) 5 pyramidal neurons of rats with freeze lesion induced malformations. These changes were associated with an increased EPSP temporal summation. Here, we examine the effects of HCN channel inhibition on synaptic responses in fast spiking, presumptive basket cells and accommodating, presumptive Martinotti, GABAergic interneurons in slices from freeze lesioned animals. In control animals, fast spiking cells showed small sag responses which were reduced by the HCN channel antagonist ZD7288. Fast spiking cells in lesioned animals showed absent or reduced sag responses. The amplitude of single evoked EPSPs in fast spiking cells in the control group was not affected by HCN channel inhibition with ZD7288. EPSP ratios during short stimulus trains at 25 Hz were not significantly different between control and lesion groups. ZD7288 produced an increase in EPSP ratios in the control but not lesion groups. Under voltage clamp conditions, ZD7288 did not affect EPSC ratios. In the control group, accommodating interneurons showed robust sag responses which were significantly reduced by ZD7288. HCN channel inhibition increased EPSP ratios and area in controls but not the lesioned group. The results indicate that HCN channels differentially modulate EPSPs in different classes of GABAergic interneurons and that this control is reduced in malformed rat neocortex.

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“…For this reason, environmental stress or exposure to excitatory toxins during this period can provoke behavioural alterations in adulthood [6], [48], [49]. The cellular and molecular bases of these long-term effects remain poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Postnatal Proteasome Inhibition Induces Neurodegeneration and Cognitive Deficiencies in Adult Mice: A New Model of Neurodevelopment Syndrome

et al. 2011

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Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation.

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Selective reductions in subpopulations of GABAergic neurons in a developmental rat model of epilepsy

Cited by 36 publications

References 46 publications

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

Progressive changes in hippocampal cytoarchitecture in a neurodevelopmental rat model of epilepsy: implications for understanding presymptomatic epileptogenesis, predictive diagnosis, and targeted treatments

HCN Channel Modulation of Synaptic Integration in GABAergic Interneurons in Malformed Rat Neocortex

Postnatal Proteasome Inhibition Induces Neurodegeneration and Cognitive Deficiencies in Adult Mice: A New Model of Neurodevelopment Syndrome

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