Developmental and genetic audiogenic seizure models: behavior and biological substrates

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Abstract

Audiogenic seizure (AGS) models of developmental or genetic origin manifest characteristic indices of generalized seizures such as clonus or tonus in rodents. Studies of seizure-resistant strains in which AGS is induced by intense sound exposure during postnatal development provide models in which other neural abnormalities are not introduced along with AGS susceptibility. A critical feature of all AGS models is the reduction of neural activity in the auditory pathways from deafness during development. The initiation and propagation of AGS activity relies upon hyperexcitability in the auditory system, particularly the inferior colliculus (IC) where bilateral lesions abolish AGS. GABAergic and glutaminergic mechanisms play crucial roles in AGS, as in temporal lobe models of epilepsy, and participate in AGS modulatory and efferent systems including the superior colliculus, substantia nigra, basal ganglia and structures of the reticular formation. Catecholamine and indolamine systems also influence AGS severity. AGS models are useful for elucidating the underlying mechanisms for formation and expression of generalized epileptic behaviors, and evaluating the efficacy of modern treatment strategies such as anticonvulsant medication and neural grafting.

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

References (151)

  • W.J. Clerici et al.

    Resting and pure tone evoked metabolic responses in the inferior colliculus of young adult and senescent rats

    Neurobiol Aging

    (1987)
  • R.W. Clough et al.

    Seizures and proto-oncogene expression of fos in the brain of adult genetically epilepsy-prone rats

    Exp Neurol

    (1997)
  • R.W. Clough et al.

    Neurite extension of developing noradrenergic neurons is impaired in genetically epilepsy-prone rats (GEPR-3s): an in vitro study on the locus coeruleus

    Epilepsy Res

    (1998)
  • J.R. Coleman et al.

    Latency alterations of the auditory brainstem response in audiogenic seizure-prone Long–Evans rats

    Epilepsy Res

    (1999)
  • A.R. Cools et al.

    The striato-nigro-collicular pathway and explosive running behaviour: functional interaction between neostriatal dopamine and collicular GABA

    Eur J Pharmacol

    (1984)
  • S.J. Czuczwar et al.

    Antagonism of N-methyl-d,l-aspartic acid-induced convulsions by antiepileptic drugs and other agents

    Eur J Pharmacol

    (1985)
  • J.W. Dailey et al.

    Effect of increments in the concentration of dopamine in the central nervous system on audiogenic seizures in DBA/2J mice

    Neuropharmacology

    (1984)
  • G. De Sarro et al.

    Gabapentin potentiates the antiseizure activity of certain anticonvulsants in DBA/2 mice

    Eur J Pharmacol

    (1998)
  • G. Ehret et al.

    Neuronal activity and tonotopy in the auditory system visualized by c-fos gene expression

    Brain Res

    (1991)
  • J.B. Eells et al.

    Expression of Fos in the superior lateral subdivision of the lateral parabrachial (LPBsl) area after generalized tonic seizures in rats

    Brain Res Bull

    (1998)
  • M.S. Evans et al.

    Loss of synaptic inhibition during repetitive stimulation in genetically epilepsy-prone rats (GEPR)

    Epilepsy Res

    (1994)
  • C.L. Faingold et al.

    Decreased effectiveness of GABA-mediated inhibition in the inferior colliculus of the genetically epilepsy-prone rat

    Exp Neurol

    (1986)
  • C.L. Faingold et al.

    GABA in the inferior colliculus plays a critical role in control of audiogenic seizures

    Brain Res

    (1994)
  • C.L. Faingold et al.

    Excitant amino acids and audiogenic seizures in the genetically epilepsy-prone rat. I. Afferent seizure initiation pathway

    Exp Neurol

    (1988)
  • C.L. Faingold et al.

    Neuronal response abnormalities in the inferior colliculus of the genetically epilepsy-prone rat

    Electroencephalogr Clin Neurophysiol

    (1986)
  • C.L. Faingold et al.

    Audiogenic seizure severity and hearing deficits in the genetically epilepsy-prone rat

    Exp Neurol

    (1990)
  • R.S. Fisher

    Animal models of the epilepsies

    Brain Res Rev

    (1989)
  • N. Garcia-Cairasco et al.

    New insights into behavioral evaluation of audiogenic seizures. A comparison of two ethological methods

    Behav Brain Res

    (1992)
  • N. Garcia-Cairasco et al.

    Reduced exploratory activity of audiogenic seizure susceptible Wistar rats

    Physiol Behav

    (1998)
  • N. Garcia-Cairasco et al.

    Neuroethological evaluation of audiogenic seizures in hemidetelencephalated rats

    Behav Brain Res

    (1989)
  • N. Garcia-Cairasco et al.

    Possible interaction between the inferior colliculus and the substantia nigra in audiogenic seizures in Wistar rats

    Physiol Behav

    (1991)
  • N. Garcia-Cairasco et al.

    Midbrain substrates of audiogenic seizures in rats

    Behav Brain Res

    (1993)
  • N. Garcia-Cairasco et al.

    Neuroethological and morphological (Neo-Timm staining) correlates of limbic recruitment during the development of audiogenic kindling in seizure susceptible Wistar rats

    Epilepsy Res

    (1996)
  • G.R. Gates et al.

    Priming for audiogenic seizures in adult BALB/c mice

    Exp Neurol

    (1973)
  • G.R. Gates et al.

    Priming for audiogenic seizures in BALB/c mice as a function of stimulus exposure duration and age

    Exp Neurol

    (1976)
  • G.R. Gates et al.

    Effects of monaural and binaural auditory deprivation on audiogenic seizure susceptibility in BALB/c mice

    Exp Neurol

    (1973)
  • M. Giordano et al.

    Constituitive expression of glutamic acid decarboxylase (GAD) by striatal cell lines immortalized using the tsA58 allele of the SV40 large T antigen

    Cell Transplant

    (1996)
  • K.R. Henry et al.

    Unilateral and bilateral effects of acoustic priming of audiogenic seizures

    Exp Neurol

    (1971)
  • E. Hirsch et al.

    The amygdala is critical for seizure propagation from brainstem to forebrain

    Neuroscience

    (1997)
  • E. Hirsch et al.

    Positive transfer of audiogenic kindling to electrical hippocampal kindling in rats

    Epilepsy Res

    (1992)
  • V.G. Iyer et al.

    Early, but not late, antiepileptic treatment reduces relapse of sound-induced seizures in the post-ischemic rat

    Brain Res

    (1995)
  • J.B. Kelly et al.

    Sound frequency and binaural response properties of single neurons in rat inferior colliculus

    Hear Res

    (1991)
  • R.P. Kesner

    Subcortical mechanisms of audiogenic seizures

    Exp Neurol

    (1966)
  • J. Kwon et al.

    Fos-immunoreactive responses in inferior colliculi of rats with experimental audiogenic seizure susceptibility

    Epilepsy Res

    (1997)
  • P.P. Lefebvre et al.

    Kainate and NMDA toxicity for cultured developing and adult rat spiral ganglion neurons: further evidence for a glutaminergic excitatory neurotransmission at the inner hair cell synapse

    Brain Res

    (1991)
  • G. Le Gal La Salle et al.

    Audiogenic seizures evoked in DBA/2 mice induce c-fos oncogene expression into subcortical auditory nuclei

    Brain Res

    (1990)
  • Y. Li et al.

    Inferior colliculus neuronal membrane and synaptic properties in genetically epilepsy-prone rats

    Brain Res

    (1994)
  • P. Mares et al.

    N-methyl-d-aspartate (NMDA)-induced seizures in developing rats

    Dev Brain Res

    (1992)
  • C. Marescaux et al.

    Kindling of audiogenic seizures in Wistar rats: an EEG study

    Exp Neurol

    (1987)
  • R. Marianowski et al.

    N-methyl-d-aspartate receptor subunits NR1 and NR2C are overexpressed in the inferior colliculus of audiogenic mice

    Neurosci Lett

    (1995)
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