Genetically Epilepsy-Prone Rats Display Anxiety-Like Behaviors and Neuropsychiatric Comorbidities of Epilepsy

Abstract

Epilepsy is associated with a variety of neuropsychiatric comorbidities, including both anxiety and depression. Despite high occurrences of depression and anxiety seen in human epilepsy populations, little is known about the etiology of these comorbidities. Experimental models of epilepsy provide a platform to disentangle the contribution of acute seizures, genetic predisposition, and underlying circuit pathologies to anxious and depressive phenotypes. Most studies to date have focused on comorbidities in acquired epilepsies; genetic models, however, allow for the assessment of affective phenotypes that occur prior to onset of recurrent seizures. Here, we tested male and female genetically epilepsy-prone rats (GEPR-3s) and Sprague-Dawley controls in a battery of tests sensitive to anxiety-like and depressive-like phenotypes. GEPR-3s showed increased anxiety-like behavior in the open field test, elevated plus maze, light-dark transition test, and looming threat test. Moreover, GEPR-3s showed impaired prepulse inhibition of the acoustic startle reflex, decreased sucrose preference index, and impaired novel object recognition memory. We also characterized defense behaviors in response to stimulation thresholds of deep and intermediate layers of the superior colliculus (DLSC), but found no difference between strains. In sum, GEPR-3s showed inherited anxiety, an effect that did not differ significantly between sexes. The anxiety phenotype in adult GEPR-3s suggests strong genetic influences that may underlie both the seizure disorder and the comorbidities seen in epilepsy.

The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats

“…The lack of effect may be due to a ceiling effect since the intact animals stayed frozen during the entire test period and for most of the poststimuli period. Aguilar et al (Aguilar et al 2018) showed intact Sprague-Dawley rats under the same LVS protocol exhibited a freezing response profile that was similar to our findings in the Long Evans rats. We cannot rule out the possibility that other tests of fear conditioning might reveal an inhibitory effect of ovariectomy on fear extinction in these normotensive rats.…”

“…The LVS test was conducted as previously described (Aguilar et al 2018). The test uses a transparent cylindrical chamber (43.5 cm × 18.5 cm) with a computer screen located above the chamber (Dell, Round Rock, TX).…”

“…The SP test was conducted as previously described (Aguilar et al 2018;Prut and Belzung 2003). The preference for sweet solutions over tap water was assessed by measuring the intake of sucrose solution (1% sucrose-w/v) and tap water over 5 days as follows: 4 consecutive days of a 2-h exposure period to the choice of sugar water vs plain.…”

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“…As we showed in the present study, during the AuK, the initially brainstem-dependent seizures, give rise to limbic seizures dependent on forebrain and limbic structures, like amygdala, cortex, and hippocampus (Moraes et al, 2000;Romcy-Pereira and Garcia-Cairasco, 2003;Galvis-Alonso et al, 2004;Poletaeva et al, 2017). Additionally, several behavioral and physiological changes are associated with seizure susceptibility and neuropsychiatric comorbidities in WARs and other audiogenic rodent strains (Castro et al, 2017;Garcia-Cairasco et al, 2017;Poletaeva et al, 2017;Aguilar et al, 2018). Furthermore, reduced GABAergic currents were observed in CA1 pyramidal neurons of WARs (Cunha et al, 2018) and volumetric increase was detected in limbic structures of WARs, like the dorsal hippocampus and amygdala, when compared to Wistars rats (Lee et al, 2018).…”

Integration of postmortem amygdala expression profiling, GWAS, and functional cell culture assays: neuroticism-associated synaptic vesicle glycoprotein 2A (SV2A) gene is regulated by miR-133a and miR-218

“…Conditional knockout mice with decreased SV2A in hippocampus are free of epileptic seizures but show elevated levels of anxiety, as measured with the Elevated Plus Maze 59 . Genetically epilepsy-prone rats exhibit an anxiety phenotype across multiple measures prior to having developed epileptic seizures 60 .…”