Environmental enrichment improves behavioral outcome in the AY-9944 model of childhood atypical absence epilepsy.

Atypical absence seizures are drug resistant in the majority of children with Lennox-Gastaut syndrome and herald a poor neurodevelopmental outcome. Here we studied the effects of environmental enrichment, enriched housing conditions designed to stimulate sensory and motor systems in the brain, on behavioral outcome in mice treated with the cholesterol biosynthesis inhibitor AY-9944 (AY), a clinically relevant model of atypical absence epilepsy. Beginning at postnatal day (P) 2, C3H mice were treated with AY (7.5 mg/kg) every 6 days until P20 and then weaned into enriched or standard cages. After 30 days (∼P50), AY mice from the enriched housing condition exhibited less behavioral hyperactivity and anxiety, improved olfactory recognition, and spatial learning, but no significant reduction in the number of ictal discharges in comparison with their non-enriched cohorts. The beneficial effects of environmental enrichment in AY model were in some behavioral tests gender-specific in favor of males suggesting that other, possibly hormonally mediated mechanisms, may interact with the therapeutic effects of enrichment. Taken together, these data provide a starting point to derive clinical occupational therapies for improving behavioral outcome in cases of intractable childhood seizures.

Circadian profiles of focal epileptic seizures: a need for reappraisal.

Circadian rhythm of seizure is underestimated in the study of focal epilepsies. A review of the current literature revealed a clear correlation between cortical epileptogenic focus and the circadian phase of seizure peak occurrence in adult patients. A single diurnal peak at 19:00 was found in seizures originating from the occipital lobe, between 5:00 and 7:00 in frontal lobe seizures, and between 16:00 and 17:00 h in temporal lobe seizures. Two diurnal peaks, between 5:00 and 7:00, and at 23:00 are reported in seizures from the parietal lobe, and between 7:00 to 8:00 and 16:00 to 17:00 in mesial temporal onset seizures. This circadian character of seizure occurrence in focal epilepsies may not be unique to partial seizures since recent clinical and experimental data indicate that generalized seizures also demonstrate circadian effects. The clinical evidence on generalized seizures and epilepsies is not recent, but a formal integration of circadian rhythmicity in our understanding and clinical management of epilepsies may be warranted.

Severity of atypical absence phenotype in GABAB transgenic mice is subunit specific.

Overexpression of GABA(B)R1a receptors in mice (R1a(+)) results in an atypical absence seizure phenotype characterized by 3- to 6-Hz slow spike-and-wave discharges (SSWDs), reduced synaptic plasticity, and cognitive impairment. Here we tested the hypothesis that increased R1 expression causes atypical absence epilepsy and is not subunit specific. GABA(B)R1b receptors were overexpressed in mouse forebrain (R1b(+)) and confirmed by immunoblot and (3)H-CGP54626A autoradiography. The R1b(+) mice showed a reduction in hippocampal long-term potentiation and GABA(A) receptor-mediated inhibitory postsynaptic currents. R1b(+) mice manifested an electrographic, pharmacological, and behavioral phenotype consistent with atypical absence seizures, though less robust than R1a(+) in terms of SSWD duration and severity of cognitive impairment. These results suggest that abnormal GABA(B)R1b function plays a lesser role in the development of atypical absence epilepsy.

Large differences in blood measures, tissue weights, and focal areas of damage 1 year after postseizure treatment with acepromazine or ketamine.

Approximately 1 year after rats were seized as young adults with lithium (3 mEq/kg) and pilocarpine (30 mg/kg) and given acepromazine or ketamine, 18 blood measures, wet tissue weights, and detailed damage scores for 107 brain structures were completed. Compared with normal and ketamine-treated rats, acepromazine-treated seized rats (total n=54) had lighter pancreata and spleens and elevated aspartate aminotransferase and alanine aminotransferase blood levels. Even though average damage did not differ, the mosaic of brain damage completely discriminated the two seized groups. Differential effects of postseizure treatment on functions of the thyroid, pancreas, and spleen were indicated. Ketamine-treated seized rats were healthier than acepromazine-treated seized rats or normal rats. This experiment demonstrates the importance of whole-organism assessment and that the single administration of a specific drug after onset of status epilepticus can produce marked differences in the evolution of brain damage and its influence on specific organs for the rest of the animal's life.

Circadian distribution of generalized tonic-clonic seizures associated with murine succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism.

Human succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of GABA metabolism associated with motor impairment and epileptic seizures. Similarly, mice with targeted deletion of the Aldh5a1 gene (Aldh5a1(-/-)) exhibit SSADH deficiency and seizures early in life. These seizures begin as absence seizures the second week of life, but evolve into generalized convulsive seizures that increase in severity and become lethal during the fourth postnatal week. The seizures are alleviated and survival is prolonged when the mutant animals are weaned onto a ketogenic diet (KD). The persistence of spontaneous, recurrent, generalized tonic-clonic seizures in KD-treated adult Aldh5a1(-/-) mice allowed us to quantify their daily (circadian) distribution using a novel behavioral method based on the detection of changes in movement velocity. Adult KD-treated Aldh5a1(-/-) mice exhibited a seizure phenotype characterized by fits of wild running clonus accompanied by jumping and bouncing. These hypermotor seizures were largely spontaneous and occurred daily in a nonrandom pattern. The seizure rhythm showed a peak shortly after dark phase onset (2008 hours) with near-24-hour periodicity. Age-matched wild-type littermates showed no evidence of abnormal motor behavior. These new data suggest that generalized tonic-clonic seizures in Aldh5a1(-/-) mice are more frequent during a specific time of day and will provide useful information to clinicians for the treatment of seizures associated with human SSADH deficiency.

Chronobiometry of behavioral activity in the Ts65Dn model of Down syndrome.

Disruption of the sleep-wake cycle has been reported among individuals with Down syndrome (DS). Here we studied behavioral rhythms in adult male and female Ts65Dn mice, a model of DS. The overall behavioral activity of Ts65Dn and diploid (2N) littermates as defined by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), rotational behavior (TURNS), and wheel-running activity (WRA) was recorded under a 12 h:12 h light-dark photocycle. During the light phase, Ts65Dn mice exhibited higher TM, MT, CT, JFP, and WRA compared to 2N littermates. During the dark phase, Ts65Dn and 2N mice differed only in CT and WRA, with the Ts65Dn group engaging in higher levels of both. There were no gender differences for any of the behavioral variables studied. Non-linear least-squares (Cosinor) analysis of the distribution of total behavioral activity (TM) indicated that Ts65Dn mice exhibited a slightly higher mean oscillation (i.e., mesor), but significantly lower amplitude in comparison to 2N mice, suggesting that levels of TM were elevated in trisomic mice but were relatively constant throughout the photocycle. The peak of the Ts65Dn TM rhythm was significantly phase-advanced, occurring approximately 4 h earlier than 2N mice. Overall, Ts65Dn mice were hyperactive and differed significantly in daily patterns of specific behaviors from those of 2N littermates. To control for the potential confound of retinal degeneration in Ts65Dn and 2N mice, we compared and found no difference between the TM rhythm parameters of 2N and non-retinally degenerate C57/129Sv mice, suggesting that abnormal behavioral rhythmicity in Ts65Dn mice may not due to the absence of rod and cone photoreceptors. These results serve as a starting point for further investigations into the physiological basis of sleep-wake disturbances in DS patients.

Daily rhythms of seizure activity and behavior in a model of atypical absence epilepsy.

We studied daily rhythms of chronic seizure activity and behavior in adult rats and mice treated with the cholesterol biosynthesis inhibitor AY-9944 (AY) during early postnatal development. Chronic atypical absence seizures were verified in the AY-treated animals by the presence of spontaneous 5- to 6-Hz slow spike-wave discharges (SSWDs) in the neocortex. General behavioral activity, as measured by total movements (TM), movement time (MT), ambulatory movement time (AMT), time spent in center of arena (CT), jumps (JFP), and rotational behavior (TURNS), were continuously recorded under a 12-hour light:12-hour dark photocycle. The average SSWD duration in AY-treated rats varied daily, with two peaks occurring at approximately dark phase and light phase onset. Mice treated with AY exhibited significant increases in all behavioral measures during the light and dark phases, with the exception of light-phase CT, which did not differ from that of controls. Consequently, the daily rhythm of total behavioral activity (TM) exhibited a significantly higher mean oscillation (mesor) and amplitude without evidence of phase shift compared with the TM rhythm of controls. The occurrence of SSWD activity in the AY model appears to be subject to regulation by biological timing mechanisms and, furthermore, associated with motor hyperactivity that does not alter the timing of behavioral rhythmicity.

Hippocampal melatonin receptors modulate seizure threshold.

PURPOSE: The pineal hormone melatonin has been shown to enhance hippocampal excitability. We therefore investigated whether inactivation of hippocampal melatonin receptors affects behavioral seizures. METHODS: Intrahippocampal infusions were performed in rats to study the effect of different melatonin receptor antagonists on behavioral activity, EEG, and seizure susceptibility. Experiments were conducted at 2 times of the day that coincided with the peak and trough of the daily melatonin rhythm. RESULTS: Local infusion of the Mel(1b) receptor antagonist 4-phenyl-2-propionamidotetralin (4-P-PDOT) into the hippocampus, but not the overlying neocortex, significantly increased seizure latency and in some cases provided complete protection against seizure development. In addition, 4-P-PDOT suppressed open field activity and hippocampal EEG amplitude. The mixed Mel(1a)/Mel(1b) receptor antagonist luzindole also increased seizure latency but to a lesser degree than 4-P-PDOT. The behavioral effects of Mel(1b) receptor inhibition were comparable to those of the gamma-aminobutyric acid (GABA)(A) receptor agonist muscimol and were observed during the dark phase (2400-0200 h) but not the light phase (1200-1400 h) of the daily photocycle. The anticonvulsant effect of intrahippocampal infusion of 4P-P-DOT was blocked by coadministration of the GABA(A) antagonist bicuculline. CONCLUSIONS: Our results suggest that nocturnal activation of hippocampal Mel(1b) receptors depresses GABA(A) receptor function in the hippocampus and enhances seizure susceptibility.

The septohippocampal system participates in general anesthesia.

How the brain mediates general anesthesia is not known. We report that two interconnected structures in the forebrain, the medial septum and the hippocampus, participate in maintaining awareness and movements during general anesthesia. In the awake, freely behaving rat, inactivation of the medial septum or the hippocampus by local injection of a GABA(A) receptor agonist, muscimol, decreased the dose of a general anesthetic needed to induce a loss of the tail-pinch response or a loss of righting reflex. Septohippocampal inactivation also suppressed the behavioral hyperactivity or the delirium stage associated with general anesthesia. An increase and decrease of 30-50 Hz (gamma) waves in the hippocampus correlated with an increase and decrease in behavioral activity, respectively. Similar results were found for both volatile (halothane and isoflurane) and nonvolatile (propofol and pentobarbital) anesthetics. We conclude that the behavioral hyperactivity induced by a general anesthetic is mediated in part by the septohippocampal system, and that depression of the septohippocampal system increases the potency of a general anesthetic. It is suggested that more potent general anesthetics or adjuvants may be developed by maximizing the pharmacological depression of the septohippocampal system.

Ketamine Prevents Learning Impairment When Administered Immediately after Status Epilepticus Onset.

Permanent cognitive impairment is common following status epilepticus (SE) in both humans and animals. We examined the effect of the NMDA antagonist ketamine administered after SE onset on two forms of associative learning in the rat: conditioned taste aversion and fear-conditioned analgesia. Following the onset of lithium/pilocarpine-induced SE, rats were administered either ketamine (100 mg/kg) or acepromazine (25 mg/kg). Acepromazine-treated animals show marked deficits in both learning measures at 1 month after SE. In contrast, ketamine-treated and nonepileptic control animals did not differ in performance for either task. Although studies have shown that ketamine is ineffective at controlling electrographic seizures early in SE, these results are consistent with previous studies showing that ketamine can preserve learning proficiency if administered shortly after seizure onset. As a clinically available drug, ketamine may prove useful in the treatment of SE when combined with conventional antiepileptic strategies.