Research reportSocial deficits in the AY-9944 mouse model of atypical absence epilepsy
Highlights
▸ Psychiatric comorbidities are a major concern in atypical absence epilepsy (AAE). ▸ Administration of AY-9944 can produce a mouse model of AAE. ▸ AY-treated mice show spontaneous and recurrent spike-and-wave discharge (4–5 Hz). ▸ Severe social deficits, but normal anxiety, were found in the AY model of AAE.
Introduction
Absence epilepsy is characterized by bilaterally synchronous spike-and-wave discharges (SWD) in electroencephalogram (EEG), and two types of absence epilepsy are observed both clinically in children and experimentally in animals [1], [2], [3], [4]. In humans, typical absence epilepsy is characterized by a distinct SWD at a frequency of 3 Hz that is associated with paroxysmal loss of consciousness or decrease in consciousness; in experimental models of typical absence epilepsy, a frequency of 7–9 Hz is observed [4], [5], [6]. Experimentally and clinically, typical absence epilepsy does not involve the hippocampus, is constrained within the thalamocortical circuitry [7], [8], and usually has a benign outcome [9]. In contrast, atypical absence epilepsy (AAE) is clinically distinct from the typical form in terms of EEG manifestations, ictal behavior, and behavioral outcomes [9], [10], [11]. The epileptic activity in AAE involves limbic circuitry, including the hippocampus, as well as thalamocortical circuitry [1], [12], [13]. The frequency of SWD in AAE is slower than 3 Hz [1], [9], [14]. Although during the ictus, voluntary movement and partial consciousness are maintained in AAE, severe cognitive and neurodevelopmental impairments have been reported [2], [14], [15].
Experimentally, an animal model of AAE can be developed with a single or repeated postnatal administration of AY-9944 (AY), a cholesterol biosynthesis inhibitor, which inhibits the reduction of 7-dehydrocholesterol to cholesterol and induces recurrent atypical absence seizures through the animal's life [1], [16], [17], [18], [19]. However, the neural mechanism of seizure development as a result of AY administration during postnatal development remains largely unknown. Nevertheless, the AY model has been shown to be a valid model of AAE. Based on EEG features (slow SWD at a frequency of 5–6 Hz in rats and 4–5 Hz in mice) and ictal behaviors as well as on pharmacological, cognitive, and developmental profiles [1], [20], [21], this model has a similar phenotype to human AAE. AY-treated rats can move or exhibit voluntary behavior during bursts of slow SWD derived from both thalamocortical and hippocampal circuitries [1], [13], [20], [22]. Thus, the AY model appears to be appropriate for the study of AAE.
Clinically, AAE is often found as a major component of Lennox–Gastaut syndrome, a malignant childhood epileptic disorder [15], [23], [24], [25], [26]. Lennox–Gastaut syndrome is also associated with mental retardation and severe behavioral outcomes, including hyperactivity, inattention, aggressiveness, and autistic tendencies [23], [27], [28], [29]. Worse, it is largely refractory to antiepileptic medications [2], [14], [23], [24].
Thus, efforts have been made to understand AAE. However, social behaviors, such as social interactions, social learning, and aggression, have rarely been examined in the AY model or in patients with AAE. In this study, we investigated behavioral dysfunction in several different social-behavioral tasks in the AY mouse model of AAE to characterize social behaviors in AAE.
Section snippets
AY model generation
Male B6/129 F1 mice, obtained from breeding two inbred mice, C57BL/6J and 129S4/SvJae were used. To induce AAE, mice pups were treated with a subcutaneous dose of the cholesterol synthesis inhibitor AY-9944 (7.5 mg/kg, Tocris), every 6 days from postnatal day (P) 2 to P20 (P2, P8, P14, P20), as described previously [1], [20], [21]. Age-matched control mice were given an equivalent volume of 0.9% saline.
Mice were housed with a 12/12-h light/dark cycle and ad libitum access to food and water.
Development of the AY-induced AAE model
As reported previously [1], [21], AY treatment resulted in the development of spontaneous, recurrent, and synchronous slow SWD in AY-treated mice (n = 8) (Fig. 1A and B). The average frequency of SWD was 4–5 Hz in EEG recordings (Fig. 1C), and the total duration of SWD was 165 (±43.42) seconds per hour (Fig. 1D). The average number of SWD occurrences was 18 (± 2.62) per hour (Fig. 1E). In concomitant video-EEG monitoring, AY-treated mice did not show a relation between SWD and immobility;
Discussion
Many patients with epilepsy suffer from psychiatric comorbidities including social dysfunction. Abnormal social behavior has been a major concern in the treatment of epilepsy. AY model has been considered to be a model of AAE [1], [20], [21], and nonsocial behavioral alterations, such as learning and memory, in the AY model have been examined. However, social-behavioral dysfunction in the AY model has remained largely unknown, as it has in patients with AAE. In the present study, we
Acknowledgements
This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0014893). D. Lee was supported by the World Class University program funded by the Ministry of Education, Science and Technology (R32-2008-000-10218-0).
References (62)
- et al.
Pathophysiological mechanisms of genetic absence epilepsy in the rat
Progress in Neurobiology
(1998) - et al.
Ictal stimulus processing during spike-wave discharges in genetic epileptic rats
Behavioural Brain Research
(2003) - et al.
Differential diagnosis of staring spells in children: a video-EEG study
Pediatric Neurology
(1996) Concentration-dependent effects of AY-9944 and U18666A on sterol synthesis in brain. Variable sensitivities of metabolic steps
Biochemical Pharmacology
(1980)- et al.
Effect of long-term administration of AY-9944, an inhibitor of 7-dehydrocholesterol delta 7-reductase, on serum and tissue lipids in the rat
Journal of Lipid Research
(1968) - et al.
A chronic model of atypical absence seizures: studies of developmental and gender sensitivity
Epilepsy Research
(2002) - et al.
Paradoxical role of GABA in a chronic model of petit mal (absence)-like epilepsy in the rat
European Journal of Pharmacology
(1990) - et al.
Learning and memory impairment in rats with chronic atypical absence seizures
Experimental Neurology
(2004) - et al.
Daily rhythms of seizure activity and behavior in a model of atypical absence epilepsy
Epilepsy & Behavior
(2006) - et al.
The circuitry of atypical absence seizures in GABA(B)R1a transgenic mice
Pharmacology Biochemistry and Behavior
(2009)
Lennox–Gastaut syndrome in adulthood: clinical and EEG features
Epilepsy Research
Lennox–Gastaut syndrome: a consensus approach on diagnosis, assessment, management, and trial methodology
The Lancet Neurology
Lennox–Gastaut syndrome
Pediatric Neurology
Impact of Lennox–Gastaut syndrome (LGS) on health-related quality of life (HRQL) of patients and caregivers: literature review
Seizure
5-HT2 modulation of AY-9944 induced atypical absence seizures
Neuroscience Letters
Deletion of N-type Ca2+ channel Cav2.2 results in hyperaggressive behaviors in mice
Journal of Biological Chemistry
Impaired memory and olfactory performance in NaSi-1 sulphate transporter deficient mice
Behavioural Brain Research
Social learning in animals: sex differences and neurobiological analysis
Pharmacology Biochemistry and Behavior
GABAB receptor antagonism abolishes the learning impairments in rats with chronic atypical absence seizures
European Journal of Pharmacology
Cognitive control mechanisms, emotion and memory: a neural perspective with implications for psychopathology
Neuroscience and Biobehavioral Reviews
Emotion and episodic memory in neuropsychiatric disorders
Behavioural Brain Research
Are the dorsal and ventral hippocampus functionally distinct structures
Neuron
Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat
Neuroscience
Selective changes in thalamic and cortical GABAA receptor subunits in a model of acquired absence epilepsy in the rat
Neuropharmacology
Transgenic mice over-expressing GABABR1a receptors acquire an atypical absence epilepsy-like phenotype
Neurobiology of Disease
Influence of social isolation in the rat on serotonergic function and memory – relevance to models of schizophrenia and the role of 5-HT receptors
Neuropharmacology
Dopaminergic–neuropeptide interactions in the social brain
Trends in Cognitive Sciences
Elevated anxiety and depressive-like behavior in a rat model of genetic generalized epilepsy suggesting common causation
Experimental Neurology
The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected]
Progress in Neuro-Psychopharmacology and Biological Psychiatry
The prevention of behavioral consequences of idiopathic generalized epilepsy: evidence from rodent models
Neuroscience Letters
Endogenous opioid peptides in brain and pituitary of rats with absence epilepsy
Neuropeptides
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S.J. and J.S.S. contributed equally to this work.