title: The frequency of spontaneous seizures in rats correlates with alterations in sensorimotor gating, spatial working memory, and parvalbumin expression throughout limbic regions.
abstract: Cognitive deficits and psychotic symptoms are highly prevalent in patients with temporal lobe epilepsy (TLE). Imaging studies in humans have suggested that these comorbidities are associated with atrophy in temporal lobe structures and other limbic regions. It remains to be clarified whether TLE comorbidities are due to the frequency of spontaneous seizures or to limbic structural damage per se. Here, we used the pilocarpine model of chronic spontaneous seizures to evaluate the possible association of seizure frequency with sensorimotor gating, spatial working memory, and neuropathology throughout limbic regions. For TLE modeling, we induced a 2-h status epilepticus by the systemic administration of lithium-pilocarpine. Once spontaneous seizures were established, we tested the locomotor activity (open field), spatial working memory (eight-arm radial maze), and sensorimotor gating (prepulse inhibition of acoustic startle). After behavioral testing, the brains were sectioned for hematoxylin-eosin staining (cell density) and parvalbumin immunohistochemistry (GABAergic neuropil) in the prefrontal cortex, nucleus accumbens, thalamus, amygdala, hippocampus, and entorhinal cortex. The animal groups analyzed included chronic epileptic rats, their controls, and rats that received lithium-pilocarpine but eventually failed to express status epilepticus or spontaneous seizures. Epileptic rats showed deficits in sensorimotor gating that negatively correlated with the radial maze performance, and impairments in both behavioral tests correlated with seizure frequency. In addition to neuronal loss at several sites, we found increased parvalbumin immunostaining in the prefrontal cortex (infralimbic area), thalamus (midline and reticular nuclei), amygdala, Ammon's horn, dentate gyrus, and entorhinal cortex. These tissue changes correlated with seizure frequency and impairments in sensorimotor gating. Our work indicates that chronic seizures might impact the inhibitory-excitatory balance in the temporal lobe and its interconnected limbic regions, which could increase the likelihood of cognitive deficits and interictal psychiatric disorders.
authors.affiliation: Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo at Ribeirão Preto, Brazil. Electronic address: daniwolf.usp@gmail.com.
authors.forename: D C
authors.initials: DC
authors.lastname: Wolf
authors.affiliation: Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo at Ribeirão Preto, Brazil. Electronic address: lezioneuro@gmail.com.
authors.forename: L S
authors.initials: LS
authors.lastname: Bueno-Júnior
authors.affiliation: Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo at Ribeirão Preto, Brazil. Electronic address: cleitonbiousp@gmail.com.
authors.forename: C
authors.initials: C
authors.lastname: Lopes-Aguiar
authors.affiliation: Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo at Ribeirão Preto, Brazil. Electronic address: raqueldoval@ig.com.br.
authors.forename: R A
authors.initials: RA
authors.lastname: Do Val Da Silva
authors.affiliation: Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo at Ribeirão Preto, Brazil. Electronic address: ludykandra@gmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Kandratavicius
authors.affiliation: Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo at Ribeirão Preto, Brazil. Electronic address: jpleite@fmrp.usp.br.
authors.forename: J P
authors.initials: JP
authors.lastname: Leite
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008032:Limbic System / Q000378:metabolism / Q000503:physiopathology*; D008094:Lithium / Q000494:pharmacology; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D010320:Parvalbumins / Q000378:metabolism*; D010862:Pilocarpine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000503:physiopathology*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D055139:Sensory Gating / Q000502:physiology*; D065852:Spatial Memory / Q000502:physiology*
chemical_list: D018721:Muscarinic Agonists; D010320:Parvalbumins; D010862:Pilocarpine; D008094:Lithium
keywords: lithium–pilocarpine; parvalbumin immunohistochemistry; prepulse inhibition; psychiatric comorbidities; radial maze; temporal lobe epilepsy