Altered anxiety-related and abnormal social behaviors in rats exposed to early life seizures

Abstract

Neonatal seizures are the most common manifestation of neurological dysfunction in the neonate. The prognosis of neonatal seizures is highly variable, and the controversy remains whether the severity, duration, or frequency of seizures may contribute to brain damage independently of its etiology. Animal data indicates that seizures during development are associated with a high probability of long-term adverse effects such as learning and memory impairment, behavioral changes and even epilepsy, which is strongly age dependent, as well as the severity, duration, and frequency of seizures. In preliminary studies, we demonstrated that adolescent male rats exposed to one-single neonatal status epilepticus (SE) episode showed social behavior impairment, and we proposed the model as relevant for studies of developmental disorders. Based on these facts, the goal of this study was to verify the existence of a persistent deficit and if the anxiety-related behavior could be associated with that impairment. To do so, male Wistar rats at 9 days postnatal were submitted to a single episode of SE by pilocarpine injection (380 mg/kg, i.p.) and control animals received saline (0.9%, 0.1 mL/10 g). It was possible to demonstrate that in adulthood, animals exposed to neonatal SE displayed low preference for social novelty, anxiety-related behavior, and increased stereotyped behavior in anxiogenic environment with no locomotor activity changes. On the balance, these data suggests that neonatal SE in rodents leads to altered anxiety-related and abnormal social behaviors.

Early life seizures: Evidence for chronic deficits linked to autism and intellectual disability across species and models

“…These experiments provide additional evidence for a causal relationship between ELS and ASD/ID. Importantly, this work demonstrates that the ELS–ASD/ID relationship extends to mice, as previously reported in rats (Bernard et al, 2013; Castelhano et al, 2013; Lippman-Bell et al, 2013; Moreira et al, 2011; Sayin et al, 2004; Talos et al, 2012; Waltereit et al., 2011). This cross species validation not only adds robustness to the theory that ELS may lead to ASD/ID, but also raises questions regarding other aspects of the ELS–ASD/ID phenotype and how, mechanistically, they are expressed in mice.…”

“…Depending on age at the time of administration, PILO ELS can incur significant mortality and substantial morphological damage (Cilio et al, 2003). PILO (380 mg/kg) induced ELS in P9 Wistar rats with high mortality (37%) (PILO-P9) (Castelhano et al, 2013). PILO (200 mg/kg) on P20 was reported to induce no morphological damage (Liu et al, 1994), while others report substantial cell loss and/or axonal reorganization and significant mortality (up to 28%) (Castelhano et al, 2013; Cilio et al, 2003; Rutten et al, 2002; Sankar et al, 1998, 2000).…”

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

“…Analogous decreases in a1-and increases in a4-containing GABA A Rs have been observed in DGCs in a rat model of temporal lobe epilepsy [122,123], later shown to involve inducible early growth response factor 3 (Egr3) up-regulation of the Gabra4 minimal promoter [124]. Consistent with the similarity of the GABA A R alterations, the heightened anxiety, depression, and spatial learning deficits in epilepsy models [125][126][127][128] are also observed in rodent FAE models [60, 64,80,129,130]. Collectively, these studies provide a strong link between altered GABA A R function and the cognitive and behavioral abnormalities associated with FAE.…”

Models of hypoxia and ischemia-induced seizures

“…The task that demonstrates preferences for a novel rodent versus a novel object may identify abnormalities in socialization (Moy et al, 2004;Yang et al, 2011). Deficits in preferences for a novel rat versus a familiar rat are thought to reflect impairments in social memory and are referred to as social novelty (Moy et al, 2004;Yang et al, 2011), which has been demonstrated in rodents with autistic phenotypes Castelhano et al, 2013;Lippman-Bell et al, 2013;Lugo et al, 2014;Moy et al, 2004;Talos et al, 2012;Waltereit et al, 2011;Yang et al, 2011). While rats with neonatal hypoxic seizures did not show significant changes in a preference for sociability, indicated by greater time spent with a novel rat than a novel object, they did show deficits in social novelty, spending significantly less time interacting with a novel rat over a familiar rat compared to naïve controls, indicating an impairment in social novelty in rats with neonatal hypoxia seizure rats (Lippman-Bell et al, 2013;Talos et al, 2012).…”

“…While autistic-like behaviors have been shown in a number of neonatal seizure models Castelhano et al, 2013;Lippman-Bell et al, 2013;Moreira et al, 2011;Sayin et al, 2004;Talos et al, 2012;Waltereit et al, 2011), studies assessing social behaviors in the hypoxia-induced seizure model have been conducted recently (Lippman-Bell et al, 2013;Talos et al, 2012). In these studies, a battery of social behavior tests including open field locomotion, three-chamber social choice test and olfactory habituation/dishabituation, was used to evaluate social behaviors in Long Evans rats with neonatal hypoxia seizures at P10.…”