Dynamics of neurodegeneration in the hippocampus of Krushinsky-Molodkina rats correlates with the progression of limbic seizures

Kulikov, Alexey A.; Naumova, A. A.; Дорофеева, Н. А.; Ivlev, Andrey P; Глазова, М. В.; Chernigovskaya, E. V.

doi:10.1016/j.yebeh.2022.108846

Cited by 11 publications

(3 citation statements)

References 47 publications

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“…Consequently, some authors have suggested that seizure protection can be achieved through inhibition of GluK1 receptors (Smolders et al, 2002;Figueiredo et al, 2011), while others propose that activating these receptors represents a promising antiepileptic strategy (Khalilov et al, 2002). In any case, genetically audiogenic seizure models are increasingly considered as prospective models for human temporal lobe epilepsy (Poletaeva et al, 2017;Kulikov et al, 2022), and hence, further investigation of the GASH/Sal hippocampus, particularly following audiogenic seizure stimulation, is warranted. The prefrontal cortex is involved in the generalized seizures of various genetic rodent models, in which a decline of histamine receptors has been reported in the lateral and medial prefrontal regions in the prefrontal cortex as well as the insular and cingulate cortices (Midzyanovskaya et al, 2022).…”

Section: Abnormal Distribution Of Gluk1 Receptors Within the Gash/sal...mentioning

confidence: 99%

Delving into the significance of the His289Tyr single-nucleotide polymorphism in the glutamate ionotropic receptor kainate-1 (Grik1) gene of a genetically audiogenic seizure model

Díaz-Rodríguez,

Herrero-Turrión,

García-Peral

et al. 2024

Front. Mol. Neurosci.

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Genetic abnormalities affecting glutamate receptors are central to excitatory overload-driven neuronal mechanisms that culminate in seizures, making them pivotal targets in epilepsy research. Increasingly used to advance this field, the genetically audiogenic seizure hamster from Salamanca (GASH/Sal) exhibits generalized seizures triggered by high-intensity acoustic stimulation and harbors significant genetic variants recently identified through whole-exome sequencing. Here, we addressed the influence of the missense single-nucleotide polymorphism (C9586732T, p.His289Tyr) in the glutamate receptor ionotropic kainate-1 (Grik1) gene and its implications for the GASH/Sal seizure susceptibility. Using a protein 3D structure prediction, we showed a potential effect of this sequence variation, located in the amino-terminal domain, on the stability and/or conformation of the kainate receptor subunit-1 protein (GluK1). We further employed a multi-technique approach, encompassing gene expression analysis (RT-qPCR), Western blotting, and immunohistochemistry in bright-field and confocal fluorescence microscopy, to investigate critical seizure-associated brain regions in GASH/Sal animals under seizure-free conditions compared to matched wild-type controls. We detected disruptions in the transcriptional profile of the Grik1 gene within the audiogenic seizure-associated neuronal network. Alterations in GluK1 protein levels were also observed in various brain structures, accompanied by an unexpected lower molecular weight band in the inferior and superior colliculi. This correlated with substantial disparities in GluK1-immunolabeling distribution across multiple brain regions, including the cerebellum, hippocampus, subdivisions of the inferior and superior colliculi, and the prefrontal cortex. Notably, the diffuse immunolabeling accumulated within perikarya, axonal fibers and terminals, exhibiting a prominent concentration in proximity to the cell nucleus. This suggests potential disturbances in the GluK1-trafficking mechanism, which could subsequently affect glutamate synaptic transmission. Overall, our study sheds light on the genetic underpinnings of seizures and underscores the importance of investigating the molecular mechanisms behind synaptic dysfunction in epileptic neural networks, laying a crucial foundation for future research and therapeutic strategies targeting GluK1-containing kainate receptors.

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Section: Abnormal Distribution Of Gluk1 Receptors Within the Gash/sal...mentioning

confidence: 99%

Delving into the significance of the His289Tyr single-nucleotide polymorphism in the glutamate ionotropic receptor kainate-1 (Grik1) gene of a genetically audiogenic seizure model

Díaz-Rodríguez,

Herrero-Turrión,

García-Peral

et al. 2024

Front. Mol. Neurosci.

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“…Limbic activation would in turn trigger its own behavioral consequences [ 26 ]. As it was shown recently, a fourteen-day schedule of AGS kindling in KM rats led to evident neurodegenerative processes, such as an irreversible hippocampal loss of granular and hilar mossy cells, as well as a reduced proliferation of inferior colliculus neurons [ 27 ]. In a shorter scheme, seven-day AGS provocation design, the cell losses were rescued by autophagy [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…As it was shown recently, a fourteen-day schedule of AGS kindling in KM rats led to evident neurodegenerative processes, such as an irreversible hippocampal loss of granular and hilar mossy cells, as well as a reduced proliferation of inferior colliculus neurons [ 27 ]. In a shorter scheme, seven-day AGS provocation design, the cell losses were rescued by autophagy [ 27 ]. An overspread of epileptiform activity in the magnocellular neurons of the hypothalamus, induced by audiogenic kindling, evoked neuroendocrine changes in the hypothalamic-neurohypophysial system [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Audiogenic Seizures and Social Deficits: No Aggravation Found in Krushinsky–Molodkina Rats

Rebik,

Broshevitskaya,

Kuzhuget

et al. 2023

Biomedicines

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Epilepsy or epileptic syndromes affect more than 70 million people, often comorbid with autism spectrum disorders (ASD). Seizures are concerned as a factor for social regression in ASD. A stepwise experimental approach to this problem requires an animal model to provoke seizures and monitor subsequent behavior. We used rats of the Krushinsky–Molodkina (KM) strain as a validated inbred genetic model for human temporal lobe epilepsy, with recently described social deficiency and hypolocomotion. Generalized tonic-clonic seizures in KM rats are sound-triggered, thus being controlled events in drug-naïve animals. We studied whether seizure experience would aggravate contact deficits in these animals. Locomotor and contact parameters were registered in “the elevated plus maze”, “socially enriched open field”, and “social novelty/social preference tests” before and after sound-provoked seizures. The triple seizure provocations minimally affected the contact behavior. The lack of social drive in KM rats was not accompanied by a submissive phenotype, as tested in “the tube dominance test”, but featured with a poor contact repertoire. Here, we confirmed our previous findings on social deficits in KM rats. The contact deficiency was dissociated from hypolocomotion and anxiety and did not correlate with seizure experience. It was established that experience of rare, generalized tonic-clonic convulsions did not lead to an impending regress in contact motivation, as seen in an animal model of genetic epilepsy and comorbid social deficiency. One of the oldest animal models for epilepsy has a translational potential to study mechanisms of social behavioral deficits in future neurophysiological and pharmacological research.

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Audiogenic kindling activates glutamatergic system in the hippocampus of rats with genetic predisposition to audiogenic seizures

Aleksandrova,

Ivlev,

Kulikov

et al. 2024

Brain Research

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Dynamics of neurodegeneration in the hippocampus of Krushinsky-Molodkina rats correlates with the progression of limbic seizures

Cited by 11 publications

References 47 publications

Delving into the significance of the His289Tyr single-nucleotide polymorphism in the glutamate ionotropic receptor kainate-1 (Grik1) gene of a genetically audiogenic seizure model

Delving into the significance of the His289Tyr single-nucleotide polymorphism in the glutamate ionotropic receptor kainate-1 (Grik1) gene of a genetically audiogenic seizure model

Audiogenic Seizures and Social Deficits: No Aggravation Found in Krushinsky–Molodkina Rats

Audiogenic kindling activates glutamatergic system in the hippocampus of rats with genetic predisposition to audiogenic seizures

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