Developmental and genetic audiogenic seizure models: behavior and biological substrates
Introduction
The audiogenic seizure (AGS) model is one of several experimental models used to study epilepsy and identify underlying mechanisms. AGS animal subjects can display generalized clonic or tonic–clonic seizure activity (formerly known as grand mal seizures) in response to intense sound stimulation. The first observations of audiogenic seizures were made in 1924 in both Pavlov's laboratory in St. Petersburg (Vasiliev, 1924; in Ref. [75]) and the Wistar Institute in Philadelphia [75]. Subsequently, several laboratories, particularly in the United States, Brazil, France and Russia, have utilized the AGS model because of its convenience and usefulness in understanding mechanisms and treatment strategies for seizure disorders. In the latter regard, it has become useful for screening anticonvulsants [32], [33], [143], [145] and testing novel therapeutic strategies such as neural transplantation [17], [18], [24].
Audiogenic seizures are a type of generalized (non-focal) seizures, one of several broad categories outlined by the Commission on Classification and Terminology of the International League Against Epilepsy [26]. A second major category of epilepsy is partial (focal) seizures, including temporal lobe epilepsy [45], [134] that is modeled in animals using kindling techniques. Generalized seizures, in contrast to partial seizures, may have no specific cortical or subcortical focus from which abnormal electrical activity arises. Generalized seizures involve a loss of consciousness accompanied by alternating periods of tonicity (rigid muscle stiffness) and clonicity (rhythmic muscle spasms). Fig. 1 summarizes animal models used for the study of seizure disorders.
Audiogenic seizures require activation of brainstem auditory pathways, in which seizures are initiated largely through the midbrain inferior colliculus, but may also involve additional subcortical [55], [89], [90], [96], [97], [147] and forebrain structures [136]. Although primarily demonstrated in rodents, AGS mechanisms parallel known substrates for temporal lobe epilepsy such as GABAergic and glutaminergic systems [134]. This review will examine both developmental and genetic models of audiogenic seizures,' including behavioral components, induction procedures (priming), and recent findings in neural and biochemical mechanisms. Previous reviews of the AGS model have been restricted to evaluation of putative AGS substrates only in genetically susceptible strains, e.g. [37], [56], [117].
Section snippets
Characterization of audiogenic seizure behaviors
The progression of audiogenic seizures is strain-specific (see section below) and can be divided into several phases: wild running, clonus, and tonus. AGS-susceptible subjects will also display characteristic post-ictal behaviors. Recent findings in AGS have suggested additional behavioral abnormalities, such as in exploratory behaviors [53].
Characterization of audiogenic seizure induction and elicitation
Most strains of mice and rats possess a general inborn susceptibility to audiogenic seizures not observed in many mammals that is closely tied to postnatal auditory and motor development. Several rodent strains not initially AGS-susceptible (so-called “resistant” strains) become seizure-prone by exposure to an acoustic insult during a certain period of postnatal development called the “sensitive” or “critical” period, see Ref. [119]. This procedure, referred to as priming, effectively induces
Peripheral AGS afferent pathway
Most of the audiogenic seizure studies in the 1950s and 1960s were characterizations of AGS induction and behavioral aspects. It was not until the 1970s that the substrates of AGS became clearer, due to increased applicability of surgical, electrophysiological, and pharmacological manipulations to animal models of epilepsy. Through these methods, the role of the auditory system in the propagation of seizure behaviors was elucidated.
Susceptibility to AGS begins with the response of the inner ear
Effects of neural transplantation in the AGS model
A novel method for investigating the role of neurotransmitter systems in the AGS response is to implant selected neural tissue populations into susceptible subjects. For example, intraventricular grafts of locus coeruleus (LC) cells in GEPR-3 subjects after 6-OHDA administration reduces seizure severity [18]. Reduction of brain norepinephrine is known to increase seizure severity [70] and this effect is ameliorated by the LC graft process. Furthermore, GEPR-3 subjects with exaggerated seizures
Conclusions
The audiogenic seizure model parallels other types of generalized seizures in terms of behavioral components and neurochemical substrates (e.g. GABAergic, glutaminergic). Extensive evidence demonstrates alterations in the auditory pathways in both primed and genetically prone strains in AGS. In particular, the inferior colliculus plays a critical role in initiation and propagation of seizure activity based on experimental lesions, pharmacological manipulations and other procedures. Further
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