Comorbidities of early-onset temporal epilepsy: Cognitive, social, emotional, and morphologic dimensions

Highlights

• Early-life status epilepticus (SE) leads to alterations in emotional/anxiety-related behavior.

• Developmental SE affects sociability and social discrimination.

• Early-life SE did not alter acquisition of spatial learning, but it impaired delayed retention.

• These changes can be interpreted as psychiatric-like comorbidities.

Abstract

Epilepsy, the most common neurologic disorder in childhood, is associated with a subset of psychiatric dysfunctions, including cognitive deficits, and alterations in emotionality (e.g., anxiety and depression) and social functioning. In the present study, we evaluated an integrative set of behavioral responses, including cognitive/socio-cognitive and emotional dimensions, using a number of behavioral paradigms in the LiCl/pilocarpine model of status epilepticus (SE) in rats. The aims of the study were to examine whether SE affects: 1) non-associative learning (habituation of exploratory behavior); 2) investigatory response to an indifferent stimulus object; 3) sociability/social novelty preference; 4) social recognition or discrimination; and 4) short- and long-term memory in the Morris water maze (MWM). Finally, we investigated the morphology of key brain structures involved in the examined behavioral dysfunctions. SE did not affect habituation to an open-field arena in juvenile (P25), adolescent (P32), or adult (P80) rats. SE rats spent less time in the central part of the arena. SE adolescent rats (P32) displayed a higher number of rearings with a shorter duration. SE rats displayed a markedly attenuated investigatory response to an indifferent stimulus object. SE rats in all age groups demonstrated pronounced deficits in sociability and the preference for social novelty. In addition, SE rats spent a reduced amount of time investigating a juvenile rat upon first exposure. After 30 min re-exposure together with an additional, novel juvenile, the SE rats spent equal time investigating both juveniles. In the MWM task, acquisition was unimpaired but there was a deficit in delayed memory retention after 10 days. SE did not affect cognitive flexibility expressed by reversal learning. Together, these findings suggest that early-life SE leads to alterations in emotional/anxiety-related behavior and affects sociability/preference for social novelty and social discrimination. Early-life SE did not alter acquisition of spatial learning, but it impaired delayed retention. Using Fluoro Jade B staining performed 24 h after SE revealed apparent neurodegeneration in the dorsal hippocampus, mediodorsal thalamic nucleus and medial amygdala, brain areas that are critically involved in network underlying emotional behavior and cognitive functions.

Introduction

Epilepsy is the most common neurologic disorder in childhood and is often associated with neurobehavioral abnormalities, including cognitive and emotional dysfunction (e.g., anxiety and depression), and social interaction and communication deficits (Berg et al., 2008; Caplan, 2017; Holmes, 2015; Holmes, 2016; Holmes et al., 2015; Jones et al., 2016; Mohanraj and Brodie, 2013). In early childhood and adolescence, the peak periods for epileptic seizure onset, the prevalence of intellectual disabilities is highest and is associated with structural brain lesions (Amiet et al., 2008; Nishimura et al., 2011). Data from epidemiologic studies suggest a bidirectional relationship between several psychiatric disorders and epilepsy, highlighting common pathogenic mechanisms in both conditions (for review, see Ekinci et al., 2009; Verrotti et al., 2014). Moreover, a number of studies support a bidirectional relationship between early-life seizures (ELS) and an early neurodevelopmental syndrome, autism spectrum disorder (ASD), with an increased prevalence of ASD in children with epilepsy and of epilepsy in children with ASD (Amiet et al., 2008; Berg and Plioplys, 2012; Bernard and Benke, 2015; Brooks-Kayal, 2010; Holmes, 2015). The newly-proposed definition of epilepsy recognizes psychiatric comorbidities in epilepsy as a part of the seizure disorder that should be treated together with the seizures (for review, see Kanner, 2016). Available data suggest a higher incidence of psychiatric comorbidity in children with temporal lobe epilepsy (TLE) than in adults, but the relationship of psychopathology to TLE has been less examined in children and adolescents (for review, see Ekinci et al., 2009). Children with TLE show impaired development of emotion recognition, perceptual deficits, abnormal social-behavioral traits, and disrupted cognition with or without intellectual deficiency. In addition, high levels of anxiety, depression, and seizure frequency are risk factors for impaired cognitive function (Laurent et al., 2014; Martinos et al., 2018).

In recent years, the extensive and complex comorbidities of ELS received significant attention as an important area of research in epilepsy (for review, see Brooks-Kayal et al., 2013; Danzer, 2012; Holmes et al., 2015; Stafstrom and Benke, 2015). Experimental studies conducted in commonly used rat models of epilepsy acquired because of ELS demonstrate an increased incidence of behavioral abnormalities. These include cognitive deficits, anxiety- and depression-like behavior, and profound deficits in social domains that mimic, to a certain extent, symptoms of neuropsychiatric comorbidities often present in humans (for review, see Bernard and Benke, 2015; Brooks-Kayal et al., 2013; Casanova et al., 2014). The majority of studies demonstrating cognitive impairment mainly examined spatial cognition (for review, see Barry et al., 2016; Casanova et al., 2014; Holmes, 2005; Holmes, 2015; Karnam et al., 2009; Kubová et al., 2004; Lugo et al., 2014; Rutten et al., 2002). ELS can also lead to alterations in social behavior, however, that in some models resemble the autistic features observed in humans (Castelhano et al., 2013; Hernan et al., 2014; Holmes et al., 2015; Lippman-Bell et al., 2013; Talos et al., 2012). The social tests were mainly interpreted in terms of pure socialization, but more sensitive tests of preference for a novel versus a familiar conspecific may also reflect abnormalities in socio-cognition (Sandi and Haller, 2015; Yang et al., 2011). Animal models of epilepsy, such as the pilocarpine model of acquired TLE are useful for studying the relationship between epilepsy and behavioral dysfunction. The temporal lobe and amygdala, in particular, play crucial roles in processing the appropriate cognitive and behavioral responses to emotionally-relevant stimuli (Twining et al., 2017). Dysregulation of the amygdala-hippocampal complex and entorhinal cortex function caused by neuronal hyperexcitability may lead to psychiatric comorbidities (Adolphs, 2010). Our data from immature rats with LiCl-pilocarpine–induced SE (Li-Pilo SE) suggest mild retardation of psychomotor development and persistent learning deficits in the hippocampal-dependent Morris water maze (MWM) task. In addition, continuous video-electroencephalographic monitoring indicates that the incidence of spontaneous non-convulsive seizures tends to progress over time (Kubová and Mareš, 2013; Kubová et al., 2004).

In the present study, we evaluated an integrative set of behavioral responses, including cognitive/socio-cognitive and emotional dimensions, using a number of behavioral paradigms in the Li-Pilo model of SE induced in immature rats at various developmental stages. The aims of the study were to examine whether ELS affect later 1) non-associative learning (habituation of exploratory behavior in an open-field arena); 2) investigatory response to an indifferent stimulus object; 3) sociability/social novelty preference; 4) social recognition or discrimination; 4) short- and long-term memory in the MWM. The final aim was to investigate the key brain structures involved in the examined behavioral dysfunctions.

The animals were tested repeatedly across multiple developmental time-points. Selected behavioral paradigms covered tasks of ethologic relevance to animals that differ in terms of the type of behavior they mediate. These behaviors involve neural circuits of interacting structures such as the hippocampus, perirhinal cortex, medial prefrontal cortex, medial dorsal thalamus, striatum, and amygdala. This neural circuitry plays a critical role in acquisition, discrimination learning, storage and retrieval of various memory processes, programming of social behavior, and mediation of behaviors with motivation/incentive and affective properties (Brown and Banks, 2015; Gasbarri et al., 2014; Hitti and Siegelbaum, 2014; Ouhaz et al., 2017; Ouhaz et al., 2015; Parnaudeau et al., 2018; van den Bos, 2015).