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MWi001: Identification of Srp9 as a febrile seizure susceptibility gene

ABSTRACT: Febrile seizures (FS) are the most common type of seizures in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). Twin studies and mutations in families with complex epilepsy syndromes including FS, indicate a genetic contribution to FS susceptibility. By employing a phenotype driven genetic strategy using consomics we mapped a quantitative trait locus (QTL) for hyperthermia-induced FS susceptibility on mouse chromosome 1. Signal Recognition Particle 9 (Srp9) in the QTL was differentially expressed between parental strains, and its binding partner Srp14 was co-identified as a strong candidate gene in another FS susceptibility QTL. The SRP complex plays a key role in the synthesis of membrane proteins, such as glutamate receptors. In vivo knock-down of brain Srp9 or inhibition of protein synthesis reduced FS susceptibility. The mouse strain (CSS1) with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Down-regulation of Srp9 in hippocampal neurons reduced surface expression of AMPA receptor subunit GluA1. Consistent with a role of SRP9 in human FS, we detected increased hippocampal SRP9 expression in mTLE patients with antecedent FS. Comparing mTLE patients and healthy controls we found an association of a SRP9 promoter SNP (rs12403575 G/A) with FS and mTLE, which was replicated in FS patients. Our findings identify SRP9 as a novel FS susceptibility gene and implicate ER-dependent protein synthesis and glutamate receptor expression in the mechanism.

ORGANISM(S): Mus musculus

PROVIDER: GSE41320 | GEO | 2014/12/01

SECONDARY ACCESSION(S): PRJNA176546

REPOSITORIES: GEO

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Project description:Early childhood convulsions have been correlated with hippocampal neuron loss in patients with intractable temporal lobe epilepsy. Using a "two-hit" rat seizure model, we have shown that animals subjected to kainate (KA)- or hypoxia-induced seizures during early postnatal period showed no cell death, yet sustained more extensive neuronal death after second seizures in adulthood. An early life seizure, without causing overt cellular injury, predisposes the brain to the damaging effect of seizures in later life. Cellular and molecular changes that accompany early seizures and that lead to subsequent epileptogenesis and increased susceptibility to seizure-induced neuronal injury, however, remain poorly understood. We propose to investigate age-specific, time-dependent changes in gene expression that may underlie this priming effect of early-life seizures. We will determine the sequence of gene expression pattern in the hippocampus at various times following KA induced seizures at postnatal day (P) 15. Previous studies have shown that AMPA receptor subtype of glutamate receptors play a crucial role in the age-specific vulnerability and in the long-term epileptogenic effects of perinatal hypoxia seizures. We found that AMPA receptor antagonists block the increased susceptibility caused by early life seizures to later seizures and seizure-induced brain damage. We hypothesize that an alteration of AMPA receptor composition is one of many changes caused by early-life seizures that leads to an increase in Ca2+ permeability, which then results in cascade of downstream events and modifies array of gene expression that promote epileptogenesis and susceptibility to neuronal death in later life. We will examine three time points: 1hr, 72 hr, and 15 days following systemic KA-induced seizures at P15 as we have previously observed structural changes within the hippocampus at these time points. Within an hour of KA seizures, a marked swelling of dendrites, disassembly of dendritic microtubules and glycogen depletion are observed by electron microscopy. Within 5 days, basal dendrites of CA3 hippocampal pyramidal neurons show abnormal spine morphology and decreased branching pattern. 15 days after the seizures, aberrant growth of mossy fibers in the CA3 stratum oriens is observed in animals exposed to KA. Ten hippocampi will be pooled from five animals treated with KA (3mg/kg i.p.) and from five littermate controls injected with PBS. Animals will be decapitated and hippocampi will be rapidly dissected from the brain, flash frozen in liquid nitrogen, and stored at -80C until extraction of total RNA, which will be sent to the center. We will provide 4 tissue samples-2 controls and 2 KA, each a pool of five animals - for each time points. Mixing tissues from multiple rats will normalize single nucleotide polymorphisms and tissue heterogeneity.

Project description:Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared messenger RNA (mRNA) expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE was distinct from that found in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. We also found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

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MWi001: Identification of Srp9 as a febrile seizure susceptibility gene

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