Abstract
Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age) and tonic-clonic (3.5-4 months) phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.
Highlights
Epilepsy is a debilitating neurological disorder characterized by recurrent spontaneous seizures
Significantly less ramified cells were observed in both the molecular layer (ML) and the granule cell layer (GCL) of the dentate gyrus at 1 month, which corresponded with an increase in the percentage of intermediate cells in the ML (Fig 1G and 1H)
After having observed increased expression of inhibitory synaptic proteins during epileptogenesis in Syn2-/- mice, we evaluated chloride-ion homeostasis that modulates the efficacy of GABAergic inhibition
Summary
Epilepsy is a debilitating neurological disorder characterized by recurrent spontaneous seizures. Epileptogenic insults including traumatic brain injury, stroke or status epilepticus are often accompanied by brain inflammation, neurodegeneration, excitatory/inhibitory (E/I) imbalance, and altered hippocampal neurogenesis [3,4,5] These processes comprise a phase of epileptogenesis, which makes the brain susceptible to the generation of the first spontaneous seizure, and to the seizure progression beyond that, as well as associated neurological co-morbidities [3, 6]. The heterogeneity associated with these models still makes it difficult to clearly delineate mechanisms for the development of spontaneous seizures per se From this perspective, genetic animal models of idiopathic epilepsy provide an alternative wherein the epileptogenic phase leading up to seizures can be evaluated without the alterations associated with the initial brain insult/seizure-related brain pathology
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