6 Hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c-Fos immunoreactivity throughout the brain

ObjectiveBesides seizures, patients with epilepsy are affected by a variety of cognitive and psychiatric comorbidities that further impair their quality of life. The present study provides an in-depth characterization of the behavioral alterations induced by 6Hz corneal kindling. Furthermore, we correlate these behavioral changes to alterations in c-Fos protein expression throughout the brain following kindling. MethodsAdolescent male Naval Medical Research Institute (NMRI) mice were kindled via repetitive subconvulsive 6Hz corneal stimulations until they reached the fully kindled state (defined as 10 consecutive generalized seizures). Afterwards we performed an elaborate battery of behavioral tests and we evaluated c-Fos expression throughout the brain using immunohistochemistry. ResultsFully kindled mice display an abnormal behavioral phenotype, characterized by basal and amphetamine-induced hyperlocomotion, anhedonia, social withdrawal, and deficits in short- and long-term memory. Moreover, 6Hz corneal kindling enhances c-Fos immunoreactivity in the visual, parahippocampal, and motor cortices and the limbic system, whereas c-Fos(+) cells are decreased in the orbital cortex of fully kindled mice. SignificanceThe behavioral outcomes of 6Hz corneal kindling cluster into 3 main categories: positive symptoms, negative symptoms, and cognitive impairment. These symptoms are accompanied by c-Fos activation in relevant brain regions once the fully kindled state is established. Based on the face validity of this model, we speculate that 6Hz corneal kindling can be used to model not only pharmacoresistant limbic seizures, but also several neurobehavioral comorbidities that affect patients with epilepsy.