Infantile spasms and Down syndrome: a new animal model

Brain Research Bulletin, 2006

The action of a GABA B antagonist CGP 35348 and a GABA B agonist baclofen was studied in two models of epileptic seizures characterized by EEG spike-and-wave rhythm in freely moving immature rats. Rhythmic metrazol activity (RMA, model of human absences) was induced by low systemic dose of pentylenetetrazol (PTZ) in 18-and 25-day-old rats, epileptic after discharges (ADs, model of human myoclonic seizures) were elicited by electrical stimulation of sensorimotor cortex in rat pups 12, 18, and 25 days old. CGP 35348 (50, 100 and 200 mg/kg i.p.) suppressed RMA in both age groups in a dose-dependent manner. Simultaneously it increased the incidence of clonic seizures, potentiating thus an effect of PTZ. Baclofen (1, 3 and 6 mg/kg i.p.) augmented markedly RMA in 25-day-old rats. On the contrary, baclofen suppressed RMA in a part of 18-day-old animals. Incidence of seizures was not changed by baclofen in either age group. As ADs are concerned CGP 35348 (100 and 200 mg/kg i.p.) exhibited a proconvulsant action, baclofen (3, 6 or 12 mg/kg i.p.) was anticonvulsant, but again an irregularity of action was found in 18-day-old rats. The role of GABA B -mediated inhibition in epileptogenesis depends on the type of seizures and also on the stage of maturation.

Acta Neuropathologica Communications, 2020

The Ihara epileptic rat (IER) is a mutant model with limbic-like seizures whose pathology and causative gene remain elusive. In this report, via linkage analysis, we identified Down syndrome cell adhesion molecule-like 1(Dscaml1) as the responsible gene for IER. A single base mutation in Dscaml1 causes abnormal splicing, leading to lack of DSCAML1. IERs have enhanced seizure susceptibility and accelerated kindling establishment. Furthermore, GABAergic neurons are severely reduced in the entorhinal cortex (ECx) of these animals. Voltage-sensitive dye imaging that directly presents the excitation status of brain slices revealed abnormally persistent excitability in IER ECx. This suggests that reduced GABAergic neurons may cause weak sustained entorhinal cortex activations, leading to natural kindling via the perforant path that could cause dentate gyrus hypertrophy and epileptogenesis. Furthermore, we identified a single nucleotide substitution in a human epilepsy that would result in...

Epilepsy Research, 2003

To investigate the impact of treatment lag in infantile spasms (IS) on treatment response, occurrence of later epilepsy, and long-term cognition and behavior in patients with one single etiological entity, we examined 18 patients with Down syndrome (DS) and earlier IS retrospectively (follow-up period of 32-180 months with a mean of 85.1 months), and determined their history and present condition, in terms of previously mentioned items. There was a statistically significant correlation between treatment lag and lag to cessation of spasms (R = 0.55, P = 0.02), developmental quotient (DQ) (R = −0.75, P = 0.003), and score of autistic features (AF) (R = 0.57, P = 0.04). Moreover we found that the later the response to treatment of IS, the lower was the DQ (R = −0.86, P = 0.001) and the higher was the score of autistic features (R = 0.5, P = 0.06). A long duration of spasms also determined a low DQ (R = −0.93, P < 0.0001) and a high score of autistic features (R = 0.66, P < 0.01). All patients with persistent epilepsy (n = 5) had had a treatment lag of over 2 months. Conversely, for all children treated within 2 months (n = 8) spasms ceased within 3 months of treatment and none of them had later epilepsy. This group of patients with a treatment lag of less than 2 months had earlier treatment response (P = 0.002), higher DQ (P = 0.004) and lower score of autistic features (P = 0.006). The data stress the importance of a short treatment lag in view of mental development and prevention of later epilepsy and autistic features, and raise the question of antiepileptogenic effect in this specific condition.

Epilepsy & Behavior, 2020

Among neurotransmitter systems affected by status epilepticus (SE) in adult rats are both GABAergic systems. To analyze possible changes of GABA A and GABA B systems in developing rats lithium-pilocarpine SE was induced at postnatal day 12 (P12). Seizures were elicited by a GABA A antagonist pentylenetetrazol (PTZ) 3, 6, 9, and 13 days after SE (i.e., in P15, P18, P21, and P25 rats), and their possible potentiation by a GABA B receptor antagonist CGP46381 was studied. Pilocarpine was replaced by saline in control animals (lithium-paraldehyde [LiPAR]). Pentylenetetrazol in a dose of 50 mg/kg s.c. elicited generalized seizures in nearly all 15-day-old naive rats and in 40% of 18-day-old ones but not in older animals. After SE, PTZ no longer elicited seizures in these two younger groups, i.e., sensitivity of GABA A system was diminished. The GABA B antagonist exhibited proconvulsant effect in P15 and P18 SE as well as LiPAR rats returning the incidence of PTZ-induced seizures to values of control animals. A decrease in the incidence of minimal clonic seizures was seen in P21 LiPAR animals; these seizures in the oldest group were not affected. Change of the effect from proconvulsant to anticonvulsant (or at least to no action) took place before postnatal day 21. Both SE and LiPAR animals exhibited similar changes but their intensity differed, effects in LiPAR controls were usually more expressed than in SE rats.

Epilepsia, 2010

Infantile spasms are the classical seizure type of West syndrome. Infantile spasms often herald a dismal prognosis, due to the high probability to evolve into intractable forms of epilepsies with significant cognitive deficits, especially if not adequately treated. The current therapies-high doses of adrenocorticotropic hormone, steroids, or the c-aminobutyric acid (GABA) transaminase inhibitor vigabatrin-are often toxic and may not always be effective. The need to identify new therapies for spasms has led to the generation of a number of rodent models of infantile spasms. These include acute and chronic models of infantile spasms, with cryptogenic or symptomatic origin, many of which are based on specific etiologies. In this review, we summarize the clinical experience with treating infantile spasms and the main features of the new animal models of infantile spasms and discuss their utility in the preclinical development of new therapies for infantile spasms.

Neuroscience Letters, 2011

γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA A receptors are heteropentamers formed by assembly of multiple subunits that generate a wide array of receptors with particular distribution and pharmacological profiles. Malfunction of these receptors has been associated with the pathophysiology of epilepsy and contribute to an imbalance of excitatory and inhibitory neurotransmission. The process of epilepsy development (epileptogenesis) is associated with changes in the expression and function of a large number of gene products. One of the major challenges is to effectively determine which changes directly contribute to epilepsy development versus those that are compensatory or not involved in the pathology. Substantial evidence suggests that changes in the expression and function of GABA A receptors are involved in the pathogenesis of epilepsy. Identification of the mechanisms involved in GABA A receptor malfunction during epileptogenesis and the ability to reverse this malfunction are crucial steps towards definitively answering this question and developing specific and effective therapies.

Reviews in The Neurosciences, 2019

Infantile spasms (IS) and seizures with focal onset have different clinical expressions, even when electroencephalography (EEG) associated with IS has some degree of focality. Oddly, identical pathology (with, however, age-dependent expression) can lead to IS in one patient vs. focal seizures in another or even in the same, albeit older, patient. We therefore investigated whether the cellular mechanisms underlying seizure initiation are similar in the two instances: spasms vs. focal. We noted that in-common EEG features can include (i) a background of waves at alpha to delta frequencies; (ii) a period of flattening, lasting about a second or more-the electrodecrement (ED); and (iii) often an interval of very fast oscillations (VFO; ~70 Hz or faster) preceding, or at the beginning of, the ED. With IS, VFO temporally coincides with the motor spasm. What is different between the two conditions is this: with IS, the ED reverts to recurring slow waves, as occurring before the ED, whereas with focal seizures the ED instead evolves into an electrographic seizure, containing high-amplitude synchronized bursts, having superimposed VFO. We used in vitro data to help understand these patterns, as such data suggest cellular mechanisms for delta waves, for VFO, for seizure-related burst complexes containing VFO, and, more recently, for the ED. We propose a unifying mechanistic hypothesisemphasizing the importance of brain pH-to explain the commonalities and differences of EEG signals in IS versus focal seizures.

Epilepsy Research, 2018

Possible proconvulsant action of GABA B receptor antagonist CGP46381 was studied 3 and 13 days after status epilepticus elicited in 12-day-old rats. GABAA-dependent activity was tested by pentylenetetrazol administration and found different in 15-day-old rats after status epiolepticus but not in the older group. The interaction of the two GABAergic systems should be studied in detail.

Epilepsy Research, 1990

The distribution and kinetics of specific binding sites for ~,-hydroxybutyrate (GHB), a naturally occurring compound known to produce absence-like seizures, was studied in the brains of Wistar rats with spontaneous, bilaterally synchronous spike wave discharges (SWDs), a model of petit mal epilepsy, and non-epileptic controls using [3H]GHB autoradiography. [3H]GHB receptor binding was increased 40-60% in lateral thalamic nuclei of the epileptic animals. Kinetic analysis showed that the increase in the binding was due to an increase in density of low affinity GHB binding sites in the epileptic animals. Given the ability of GHB to produce petit mal-like seizures when administered to animals, and the fact that the SWDs in the Wistar rat model seem to emanate from lateral thalamus, these data raise the possibility that GHB-mediated mechanisms may play a role in the pathogenesis of petit mal seizures. INTRODUCTION Petit mal or generalized absence seizures are fundamentally different from any other seizure type. These seizures most commonly afflict children and are characterized electrographically by bilaterally synchronous 3 Hz spike wave discharges (SWD) associated with behavioral arrest, occasional automatisms, and the absence of an aura or postictal state 4A2'23. Generalized absence seizures are further characterized by the fact that they respond uniquely to the anticonvulsant drags

CNS Neuroscience & Therapeutics, 2014

Early in development, GABA, which is the main inhibitory neurotransmitter in adult brain, depolarizes immature neurons and exerts dual-excitatory and shunting/inhibitoryeffects in the developing neuronal networks. The present review discusses some general questions, including the properties of excitation at depolarizing GABAergic synapse and shunting inhibition by depolarizing GABA; technical issues in exploration of depolarizing GABA using various techniques and preparations, including the developmental aspects of traumatic injury and what is known (or rather unknown) on the actions of GABA in vivo; complex roles of depolarizing GABA in developmental epilepsies, including a contribution of depolarizing GABA to enhanced excitability in the immature networks, caused by repetitive seizures accumulation of intracellular chloride concentration that increases excitatory GABA power and its synchronizing proconvulsive effects, and correction of chloride homeostasis as a potential strategy to treat neonatal seizures.