Dataset Information

Maternal immune activation promotes hippocampal kindling epileptogenesis in mice.

ABSTRACT: Maternal immune activation (MIA) triggered by infections has been identified as a cause of autism in offspring. Considering the involvement of perturbations in innate immunity in epilepsy, we examined whether MIA represents a risk factor for epilepsy as well. The role of specific MIA components interleukin (IL)-6 and IL-1? was also addressed.MIA was induced in C57BL/6 mice by polyinosinic-polycytidylic acid (PIC) injected during embryonic days 12 to 16. Beginning from postnatal day 40, the propensity of the offspring to epilepsy was examined using hippocampal kindling; autismlike behavior was studied using the sociability test. The involvement of IL-6 and IL-1? in PIC-induced effects was studied by the coadministration of the cytokine antibodies with PIC, and by delivering recombinant cytokines in lieu of PIC.The offspring of PIC-exposed mice exhibited increased hippocampal excitability, accelerated kindling rate, prolonged increase of seizure susceptibility after kindling, and diminished sociability. Epileptic impairments were abolished by antibodies to IL-6 or IL-1?. Neither of the recombinant cytokines alone increased the propensity to seizures; however, when combined, they produced effects similar to those induced by PIC. PIC-induced behavioral deficits were abolished by IL-6 antibodies and were mimicked by recombinant IL-6; IL-1? was not involved.In addition to confirming the previously established critical role of IL-6 in the development of autismlike behavior following MIA, the present study shows that concurrent involvement of IL-6 and IL-1? is required for priming the offspring for epilepsy. These data shed light on mechanisms of comorbidity between autism and epilepsy.

SUBMITTER: Pineda E

PROVIDER: S-EPMC3775928 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Maternal immune activation promotes hippocampal kindling epileptogenesis in mice.

Pineda Eduardo E Shin Don D You Su Jeong SJ Auvin Stéphane S Sankar Raman R Mazarati Andréy A

Annals of neurology 20130701 1

<h4>Objective</h4>Maternal immune activation (MIA) triggered by infections has been identified as a cause of autism in offspring. Considering the involvement of perturbations in innate immunity in epilepsy, we examined whether MIA represents a risk factor for epilepsy as well. The role of specific MIA components interleukin (IL)-6 and IL-1β was also addressed.<h4>Methods</h4>MIA was induced in C57BL/6 mice by polyinosinic-polycytidylic acid (PIC) injected during embryonic days 12 to 16. Beginnin ...[more]

PMID: 23907982

Similar Datasets

Project description:Prenatal stress often results in maternal immune activation (MIA) that can impact prenatal brain development, molecular processes, and substrates and products of metabolism that participate in physiological processes at later stages of life. Postnatal metabolic and immunological stressors can affect brain metabolites later in life, independently or in combination with prenatal stressors. The effects of prenatal and postnatal stressors on hippocampal metabolites were studied using a pig model of viral MIA exposed to immunological and metabolic stressors at 60 days of age using gas chromatography mass spectrometry. Postnatal stress and MIA elicited effects (FDR-adjusted p-value < 0.1) on fifty-nine metabolites, while eight metabolites exhibited an interaction effect. The hippocampal metabolites impacted by MIA or postnatal stress include 4-aminobutanoate (GABA), adenine, fumarate, glutamate, guanine, inosine, ornithine, putrescine, pyruvate, and xanthine. Metabolites affected by MIA or postnatal stress encompassed eight significantly (FDR-adjusted p-value < 0.1) enriched Kyoto Encyclopedia of Genes and Genomes Database (KEGG) pathways. The enriched arginine biosynthesis and glutathione metabolism pathways included metabolites that are also annotated for the urea cycle and polyamine biosynthesis pathways. Notably, the prenatal and postnatal challenges were associated with disruption of the glutathione metabolism pathway and changes in the levels of glutamic acid, glutamate, and purine nucleotide metabolites that resemble patterns elicited by drugs of abuse and may underlie neuroinflammatory processes. The combination of MIA and postnatal stressors also supported the double-hit hypothesis, where MIA amplifies the impact of stressors later in life, sensitizing the hippocampus of the offspring to future challenges. The metabolites and pathways characterized in this study offer evidence of the role of immunometabolism in understanding the impact of MIA and stressors later in life on memory, spatial navigation, neuropsychiatric disorders, and behavioral disorders influenced by the hippocampus.

Project description:ObjectiveTissue remodeling has been described in brain circuits that are involved in the generation and propagation of epileptic seizures. Human and animal studies suggest that the anterior piriform cortex (aPC) is crucial for seizure expression in focal epilepsies. Here, we investigate the effect of kainic-acid (KA)-induced seizures on the effective connectivity of the aPC with bilateral hippocampal CA3 regions using cerebro-cerebral evoked potentials (CCEPs).MethodsAdult male Sprague-Dawley rats were implanted with a tripolar electrode in the left aPC for stimulation and recording, and with unipolar recording electrodes in bilateral CA3 regions. Single pulse stimulations were given to the aPC and CCEPs were averaged before KA injections and after the emergence of spontaneous recurrent seizures (SRS). Similar recordings at equivalent time intervals were obtained from animals that received saline injections instead of KA (controls).ResultsIn the experimental group, the percentage change of increased amplitude of the contralateral (but not ipsilateral) CA3 CCEPs between pre-KA injection and after the emergence of SRS was significantly greater than in controls. No significant single-pulse-induced spectral change responses were observed in either epileptic or control rats when comparing pre- and post-stimulus time intervals. Also, we found no correlation between seizure frequency and the extent of amplitude changes in the CCEPs.ConclusionsIn the KA model, epileptogenesis results in plastic changes that manifest as an amplification of evoked potential amplitudes recorded in the contralateral hippocampus in response to single-pulse stimulation of the aPC. These results suggest epileptogenesis-induced facilitation of interhemispheric connectivity between the aPC and the hippocampus. Since the amplitude increase of the contralateral CCEP is a possible in vivo biomarker of epilepsy, any intervention (e.g. neuromodulatory) that can reverse this phenomenon may hold a potential antiepileptic efficacy.

Project description:Epilepsy is a common neurological disorder characterized by naturally-occurring spontaneous recurrent seizures and comorbidities. Kindling has long been used to model epileptogenic mechanisms and to assess antiepileptic drugs. In particular, extended kindling can induce spontaneous recurrent seizures without gross brain lesions, as seen clinically. To date, the development of spontaneous recurrent seizures following extended kindling, and the effect of the antiepileptic drugs on these seizures are not well understood. In the present study we aim to develop a mouse model of extended hippocampal kindling for the first time. Once established, we plan to evaluate the effect of three different antiepileptic drugs on the development of the extended-hippocampal-kindled-induced spontaneous recurrent seizures. Male C57 black mice were used for chronic hippocampal stimulations or handling manipulations (twice daily for up to 70 days). Subsequently, animals underwent continuous video/EEG monitoring for seizure detection. Spontaneous recurrent seizures were consistently observed in extended kindled mice but no seizures were detected in the control animals. The aforementioned seizures were generalized events characterized by hippocampal ictal discharges and concurrent motor seizures. Incidence and severity of the seizures was relatively stable while monitored over a few months after termination of the hippocampal stimulation. Three antiepileptic drugs with distinct action mechanisms were tested: phenytoin, lorazepam and levetiracetam. They were applied via intra-peritoneal injections at anticonvulsive doses and their effects on the spontaneous recurrent seizures were analyzed 10-12 h post-injection. Phenytoin (25 mg/kg) and levetiracetam (400 mg/kg) abolished the spontaneous recurrent seizures. Lorazepam (1.5 mg/kg) decreased motor seizure severity but did not reduce the incidence and duration of corresponding hippocampal discharges, implicating its inhibitory effects on seizure spread. No gross brain lesions were observed in a set of extended hippocampal kindled mice submitted to histological evaluation. All these data suggests that our model could be considered as a novel mouse model of extended hippocampal kindling. Some limitations remain to be considered.

Dataset Information

Maternal immune activation promotes hippocampal kindling epileptogenesis in mice.

Publications

Maternal immune activation promotes hippocampal kindling epileptogenesis in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets