Epilepsy-associated alterations in hippocampal excitability

Navidhamidi, Mojdeh; Ghasemi, Maedeh; Mehranfard, Nasrin

doi:10.1515/revneuro-2016-0059

Cited by 40 publications

(20 citation statements)

References 343 publications

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“…Consistent with this finding, ELOVL4 expression is high in the CA3 region of the hippocampus and the entorhinal cortex, which give rise to the Schaffer collaterals and perforant path, respectively. The hippocampus has well-established links to many different types of seizure disorders, including medial temporal lobe epilepsy [ 52 , 53 ]. This is due to the hippocampus serving as a major point of connection to cortex-associated regions that allows and facilitates the spread of epileptiform activity between cortical and hippocampal networks.…”

Section: Resultsmentioning

confidence: 99%

Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

et al. 2017

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Lipids are essential components of the nervous system. However, the functions of very long-chain fatty acids (VLC-FA; ≥ 28 carbons) in the brain are unknown. The enzyme ELOngation of Very Long-chain fatty acids-4 (ELOVL4) catalyzes the rate-limiting step in the biosynthesis of VLC-FA (Agbaga et al., Proc Natl Acad Sci USA 105(35): 12843–12848, 2008; Logan et al., J Lipid Res 55(4): 698–708, 2014), which we identified in the brain as saturated fatty acids (VLC-SFA). Homozygous mutations in ELOVL4 cause severe neuropathology in humans (Ozaki et al., JAMA Neurol 72(7): 797–805, 2015; Mir et al., BMC Med Genet 15: 25, 2014; Cadieux-Dion et al., JAMA Neurol 71(4): 470–475, 2014; Bourassa et al., JAMA Neurol 72(8): 942–943, 2015; Aldahmesh et al., Am J Hum Genet 89(6): 745–750, 2011) and are post-natal lethal in mice (Cameron et al., Int J Biol Sci 3(2): 111–119, 2007; Li et al., Int J Biol Sci 3(2): 120–128, 2007; McMahon et al., Molecular Vision 13: 258–272, 2007; Vasireddy et al., Hum Mol Genet 16(5): 471–482, 2007) from dehydration due to loss of VLC-SFA that comprise the skin permeability barrier. Double transgenic mice with homozygous knock-in of the Stargardt-like macular dystrophy (STDG3; 797-801_AACTT) mutation of Elovl4 with skin-specific rescue of wild-type Elovl4 expression (S + Elovl4 mut/mut mice) develop seizures by P19 and die by P21. Electrophysiological analyses of hippocampal slices showed aberrant epileptogenic activity in S + Elovl4 mut/mut mice. FM1-43 dye release studies showed that synapses made by cultured hippocampal neurons from S + Elovl4 mut/mut mice exhibited accelerated synaptic release kinetics. Supplementation of VLC-SFA to cultured hippocampal neurons from mutant mice rescued defective synaptic release to wild-type rates. Together, these studies establish a critical, novel role for ELOVL4 and its VLC-SFA products in regulating synaptic release kinetics and epileptogenesis. Future studies aimed at understanding the molecular mechanisms by which VLC-SFA regulate synaptic function may provide new targets for improved seizure therapies.Electronic supplementary materialThe online version of this article (10.1007/s12035-017-0824-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

et al. 2017

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“…8A). In the hippocampus, a known locus for temporal medial lobe seizures (Navidhamidi et al, 2017; Soussi et al, 2015), ELOVL4 expression was very strong in CA3 and the polymorphic layer of the dentate gyrus (DG), as well as in the subiculum and entorhinal cortex, which provide synaptic input to the hippocampal circuit. The neurons to which DG projects in CA2 and CA1 regions showed weaker ELOVL4 labeling (Hopiavuori et al, 2017b; Sherry et al, 2017) (Fig.…”

Section: Understanding the Role Of Elovl4 In The Cns; A Shift To In Vmentioning

confidence: 99%

ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

Hopiavuori

Anderson

Agbaga

2019

Progress in Retinal and Eye Research

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ELO ngation of V ery L ong chain fatty acids- 4 (ELOVL4) is an elongase responsible for the biosynthesis of very long chain (VLC, ≥C28) saturated (VLC-SFA) and polyunsaturated (VLC-PUFA) fatty acids in brain, retina, skin, Meibomian glands, and testes. Fascinatingly, different mutations in this gene have been reported to cause vastly different phenotypes in humans. Heterozygous inheritance of seven different mutations in the coding sequence and 5’ untranslated region of ELOVL4 causes autosomal dominant Stargardt-like macular dystrophy (STGD3), while homozygous inheritance of three more mutant variants causes severe seizures with ichthyosis, hypertonia, and even death. Some recent studies have described heterozygous inheritance in yet another three mutant ELOVL4 variants, two that cause spinocerebellar ataxia-34 (SCA34) with erythrokeratodermia (EKV) and one that causes SCA34 without EKV. We identified the specific enzymatic reactions catalyzed by ELOVL4 and, using a variety of genetically engineered mouse models, have actively searched for the mechanisms by which ELOVL4 impacts neural function and health. In this review, we critically compare and contrast the various animal model and case studies involving ELOVL4 deficiency via either mutation or deletion, and the resulting consequences on neuronal health and function in both the retina and central nervous system.

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“…Taking into account these EEG alterations and the fact that hyperexcitability affects the susceptibility to seizures (Navidhamidi et al, 2017), we also tested the propensity of FoxG1 +/mice to develop behaviorally detectable seizures in response to a single i.p. administration of a proconvulsant, namely kainic acid (KA).…”

Section: Hippocampal Hyperexcitability In Foxg1 +/− Mice Is Rescued Bmentioning

confidence: 99%

A triheptanoin-supplemented diet rescues hippocampal hyperexcitability and seizure susceptibility in FoxG1 mice

et al. 2019

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The Forkhead Box G1 (FOXG1) gene encodes a transcription factor with an essential role in mammalian telencephalon development. FOXG1-related disorders, caused by deletions, intragenic mutations or duplications, are usually associated with severe intellectual disability, autistic features, and, in 87% of subjects, epileptiform manifestations. In a subset of patients with FoxG1 mutations, seizures remain intractable, prompting the need for novel therapeutic options. To address this issue, we took advantage of a haploinsufficient animal model, the FoxG1 +/− mouse. In vivo electrophysiological analyses of FoxG1 +/− mice detected hippocampal hyperexcitability, which turned into overt seizures upon delivery of the proconvulsant kainic acid, as confirmed by behavioral observations. These alterations were associated with decreased expression of the chloride transporter KCC2. Next, we tested whether a triheptanoin-based anaplerotic diet could have an impact on the pathological phenotype of FoxG1 +/− mice. This manipulation abated altered neural activity and normalized enhanced susceptibility to proconvulsant-induced seizures, in addition to rescuing altered expression of KCC2 and increasing the levels of the GABA transporter vGAT. In conclusion, our data show that FoxG1 haploinsufficiency causes dysfunction of hippocampal circuits and increases the susceptibility to a proconvulsant insult, and that these alterations are rescued by triheptanoin dietary treatment.

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Epilepsy-associated alterations in hippocampal excitability

Cited by 40 publications

References 343 publications

Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

Homozygous Expression of Mutant ELOVL4 Leads to Seizures and Death in a Novel Animal Model of Very Long-Chain Fatty Acid Deficiency

ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

A triheptanoin-supplemented diet rescues hippocampal hyperexcitability and seizure susceptibility in FoxG1 mice

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