Developmental and genetic audiogenic seizure models: behavior and biological substrates

NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS

PERGAMON

Neuroscience and Biobehavioral Reviews 24 (2000) 639±653

www.elsevier.com/locate/neubiorev

Developmental and genetic audiogenic seizure models: behavior and biological substrates K.C. Ross a, J.R. Coleman a,b,* a

b

Department of Psychology, University of South Carolina, Columbia, SC 29208, USA Department of Pharmacology and Physiology, University of South Carolina School of Medicine, Columbia, SC 29208, USA Received 22 March 1999; received in revised form 20 December 1999; accepted 15 May 2000

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 in¯uence AGS severity. AGS models are useful for elucidating the underlying mechanisms for formation and expression of generalized epileptic behaviors, and evaluating the ef®cacy of modern treatment strategies such as anticonvulsant medication and neural grafting. q 2000 Elsevier Science Ltd. All rights reserved. Keywords: Epilepsy; Audiogenic seizure; Inferior colliculus; Cochlea; Priming; Reticular formation; Clonus; Tonus

1. 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 ®rst 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)

* Corresponding author. Tel.: 11-803-777-7152; fax: 11-803-777-9558. E-mail address: [email protected] (J.R. Coleman).

seizures, one of several broad categories outlined by the Commission on Classi®cation 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 speci®c 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 ®ndings in neural and biochemical mechanisms.

0149-7634/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved. PII: S 0149-763 4(00)00029-4

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Previous reviews of the AGS model have been restricted to evaluation of putative AGS substrates only in genetically susceptible strains, e.g. Refs. [37,56,117]. 2. Characterization of audiogenic seizure behaviors The progression of audiogenic seizures is strain-speci®c (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 ®ndings in AGS have suggested additional behavioral abnormalities, such as in exploratory behaviors [53]. 2.1. Wild running Wild running is a reliable component of an audiogenic seizure, regardless of the ®nal severity level achieved (Table 1). In the wild running phase, subjects run at full speed uncontrollably in the testing chamber some time after acoustic stimulation begins. The wild running phase may give way to clonic or tonic±clonic convulsions (a twocomponent seizure), or clonic/tonic±clonic convulsions followed by an additional tonic convulsion phase (a threecomponent seizure). The wild running phase itself may consist of one or two distinct running bouts, and is typically considered to be part of the seizure progression, although this distinction is not evident or has not been reported in rodents such as the C57B1/6J mouse [62]. Reid and Collins [110] observed that interruption of acoustic stimulation prior to the ®rst wild running phase delayed wild running when stimulation was restarted, as if subjects (SJL/J mice) had begun a new behavioral test. Reintroduction of the stimulus within a few seconds after interruption during the ®rst wild running phase resulted in additional wild running

or convulsions. Convulsions occurred less frequently if the interruption occurred close to or during the second wild run [110], suggesting that the second wild running phase is more closely tied to convulsions than the ®rst wild running phase. Subjects can return to seizure activity if acoustic interruption occurs early in the progression, but not later. According to the Jobe Audiogenic Response Score (ARS), an index of audiogenic seizure severity, one wild running phase is rated higher than two phases, as is a seizure preceded by one wild run instead of two [70]. The brief period of inactivity separating wild running phases (about 15 s; Ref. [110]) is proposed to represent a form of inhibition [47]. In fact, the ®rst wild run has been described in the literature as a ªfalse startº of AGS progression [47]. Further acoustic stimulation is required for wild running to resume and culminate in convulsions, which provides evidence for the decreased severity of two wild runs as compared to one. Mice tested for AGS with a glycerin-occluded ear typically displayed two wild running bouts before the onset of convulsions, while mice tested without an occluded ear displayed only one wild running bout before convulsions [109,112]. Lastly, one wild running phase was more often associated with tonic-level seizures in mice [111]. Several strains of mice and rats will display either one or two wild running phases [73,109,113]. However, several reports of audiogenic seizure activity fail to mention the speci®c occurrence of uniphasic (one-phase) or biphasic (two-phase) wild running, making it impossible to speculate on possible underlying mechanisms that account for differences in wild running activity. At seizure-inducing stimulus intensity levels, wild running latencies (latency from stimulus onset to the initiation of wild running) can range from approximately 2 s in severe genetically epilepsy-prone rats (GEPR-9; Ref. [92]) to more than 20 s in Long±Evans rats

Fig. 1. Simpli®ed scheme of experimental models of epilepsy. a The WAR and GEPR rat strains and DBA mice strain may also be placed under the ªGeneticº category, but this was omitted for the sake of simplicity. GEPR ˆ genetically epilepsy-prone rat. WAR ˆ Wistar audiogenic rat. L±E ˆ Long±Evans rat. S±D ˆ Sprague±Dawley rat.

K.C. Ross, J.R. Coleman / Neuroscience and Biobehavioral Reviews 24 (2000) 639±653 Table 1 AGS behavioral components displayed by rodent strain Strain

Wild running

Rat Primed Wistar p Sprague±Dawley p Long±Evans p Genetically susceptible WAR b p GEPR-3 p GEPR-9 p Mouse Primed SJL p C57 p BALB/c p Genetically susceptible DBA p a b

Clonus

Tonus

Reference

p

Wa

[106] [103] [119]

p

[56] [91] [92]

p p p p

p p p

p p

[109] [62] [127]

p

p

[109]

Tonic extension with partial tonic hindlimb extension. Wistar audiogenic rat.

[124]. Wild running latencies for several AGS-susceptible strains are summarized in Table 2. 2.2. Clonus Clonic convulsions, which occur after the wild running phase, are characterized by ¯exion of the dorsal surface (back), neck, forelimbs, and hindlimbs, accompanied by full-body muscle spasms and rocking motions. The clonic convulsions may be separated by moments of full-body rigidity (tonus); with this observation, the seizure would be classi®ed as tonic±clonic. For some strains of rats, including the Wistar [43,107], Sprague±Dawley [103], Long±Evans [69,113,119] and the moderate genetically epilepsy-prone rat (GEPR-3; Ref. [91]), a clonic or tonic± clonic convulsion represents the maximal seizure severity attainable. At seizure-inducing stimulus intensity levels, the latency to clonic convulsions varies from nearly 10 s in DBA/2J mice [112] to more than 30 s in Long±Evans rats [119]. Latencies to clonus among rodent strains are summarized in Table 2. In the Long±Evans rat, the average duration of clonus is over 20 s [119]. Clonus duration has not been routinely reported in previous AGS literature. 2.3. Tonus The most severe manifestation of AGS is tonus, which consists of sustained rigid extension of the dorsal surface, neck, forelimbs, and hindlimbs, in contrast to the ¯eeting tonus of a tonic±clonic seizure. Because of the dorsoextension, the subject's ventral surface is ¯exed, so this type of seizure posture may also be referred to as ventro¯exion. The subject's body in a tonic seizure assumes an arched shape. A tonic-level audiogenic seizure is always preceded by wild running and possibly clonic-level convulsions, and may lead

641

Table 2 Mean AGS wild running/clonus latencies from stimulus initiation by rodent strain ( p indicates data unavailable) Strain

Latency (s)

Reference

Rat GEPR-9 GEPR-3 WAR Long±Evans Wistar (genetic) Wistar (primed)

1.6±2.2/ p 6.5±7.5/13.5±17 15.4/60.1 23.59 (1st) a, 40.3 (2nd)/39.25 p /5±40 5.2/ p

[92] [91] [54] [119] [73] [107]

2.75±5.6/5.6±8.2 2.1±2.4 (median)/ p p /4.8±11 3.8/9.5 4±13/ p 17 (1st), 46 (2nd)/51.50 b/ 16.82 c/50.17 d 10±20/ p

[127] [14] [59] [112] [65] [111]

Mouse BALB/c DBA/2J SJL C57

[65]

a

Ref. [124]. Clonus latency for SJL mice exhibiting a biphasic (two wild run) audiogenic seizure. c Clonus latency for SJL mice exhibiting a uniphasic (one wild run) audiogenic seizure with a latency less than 30 s. d Clonus latency for SJL mice exhibiting a uniphasic (one wild run) audiogenic seizure with a latency greater than 30 s. b

to death, which is more common in mice strains, e.g. Refs. [14,62,130]. Tonic seizures are observed in rodent strains such as DBA/2J mice [112], GEPR-9 rats [92], and Wistar rats inbred for AGS susceptibility [54,73]. Reported latencies to tonus vary from approximately 4 s in GEPR-9 rats [92] to 11 s in DBA/2J mice [112]. Tonic seizure duration in inbred Wistar rats approximates 20 s [73]. The sparse characterization of tonic-level AGS re¯ects a level of seizure severity restricted mainly to certain genetically-prone rodent strains. 2.4. Post-ictal behaviors After a clonic, tonic±clonic, or tonic-level seizure, subjects usually display behaviors typical of a post-ictal period, including immobility [51] and vocalization [140]. A short period of unresponsiveness to further acoustic or tactile stimulation may also occur post-ictally. Subjects may be responsive to acoustic stimulation as soon as 15 min after the post-ictal period (Ross, unpublished observations). 2.5. Strain differences in AGS progression All strains of mice and rats that are used in audiogenic seizure research (Fig. 1) display at least wild running in response to acoustic stimulation. For susceptible Sprague± Dawley rats, this is the modal AGS severity level displayed [103]. For most strains, varying levels of maximal seizure severity can be displayed (Table 1), usually clonus or tonus.

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The severity level achieved depends on several factors, including external stimulus factors, such as continuous or discontinuous stimulation [110], stimulus intensity [119], and occlusion of the external meatus of the ear [109]. Differences in AGS activity can be observed even without changes in stimulation parameters; Ross and Coleman [119] observed clonic convulsions preceded by either one or two wild running phases in Long±Evans rats. Individual subjects were also inconsistent in the number of wild runs displayed before convulsions with repeated testing over a period of days or weeks (Ross, unpublished observations). Thus, several factors must be considered in accounting for the number of wild running phases displayed by AGSsusceptible subjects. Few comparative studies of AGS severity have been conducted; available studies have been restricted to susceptible mouse strains [64,65]. Until this critical integration occurs, the continued use of a variety of rodent strains in AGS research will help characterize the underlying neuroanatomical and neurochemical substrates for each level of AGS severity. 2.6. Associated behaviors of AGS-susceptible subjects It has been shown that AGS-susceptible subjects show additional behavioral abnormalities, such as reduced overall exploratory activity. In an AGS testing chamber, genetically AGS-susceptible Wistar rats [50] show reduced exploratory activity compared to seizure-resistant rats before and during sound stimulation. Resistant rats will walk around the test chamber before and during sound stimulation [51,54,140], while susceptible rats will be relatively immobile prior to the initiation of seizure activity [51]. When tested in an open arena or elevated plus maze, susceptible rats show less exploratory behavior [53], which suggests higher anxiety levels than seizure-resistant controls [53]. 3. 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 AGSsusceptible (so-called ªresistantº strains) become seizureprone by exposure to an acoustic insult during a certain period of postnatal development called the ªsensitiveº or ªcriticalº period, see Ref. [119]. This procedure, referred to as priming, effectively induces AGS susceptibility as ®rst reported by Henry [62] and Iturrian and colleagues [68]. During the priming procedure, subjects will not display seizure behavior. After a strain-dependent period of time, primed subjects tested with an intense stimulus will display wild running and clonic, tonic±clonic, or tonic seizures (Table 1). For genetically prone strains of mice and rats, no priming procedure is required; audiogenic

seizures are elicited by intense sound as early as 3 weeks after birth [91,92]. 3.1. Genetic models of audiogenic seizures A few strains of rats (GEPR, WARÐthe Wistar Audiogenic Rat) and at least one strain of mouse (DBA) are genetically susceptible to audiogenic seizures. Both GEPR substrains (GEPR-3 and GEPR-9) originated at the University of Arizona in the late 1950s [114]. Initially, Sprague± Dawley rats were selectively bred based on their innate moderate (3) or maximal (9) seizure severity level according to the Jobe Audiogenic Response Score [70]. The Arizona GEPR colony was discontinued in the mid-1980s [114] and animals moved to Northeast Louisiana University where GEPR-3 rats were combined with a GEPR-3 colony started by Jobe in 1971 and GEPR-9s maintained as a separate substrain. Both GEPR colonies were moved to the University of Illinois College of Medicine in 1985 [114]. The standard GEPR protocol is to test subjects for audiogenic seizures three times before experimental inclusion, once a week after the females of the litter reach a body weight of 100 g [114]. In addition to AGS susceptibility, GEPR substrains show lowered thresholds for other types of seizures induced by convulsants or hyperthermia [41]. The genetically-susceptible WAR strain, bred from selective brother±sister matings among Wistar rats susceptible to audiogenic seizures [50] at the Ribeirao Preto School of Medicine in Sao Paulo, Brazil, displays tonic±clonic seizure behavior in response to an acoustic challenge. The DBA mouse strain is also genetically AGS-susceptible, but only for a certain developmental period beginning on approximately postnatal day (PND) 12 and lasting until approximately PND 42 [131]. DBA mice will display clonic and tonic-level audiogenic seizures. These data suggest that AGS expression requires a minimum maturational level of the auditory pathway. 3.2. Primed models of audiogenic seizures For resistant strains of rats and mice that are primed for AGS susceptibility, certain stimulation parameters are critical, such as day of priming, day of testing, and stimulus intensity for both priming and testing (Table 3). Another important parameter is the frequency of the priming and testing stimulus. The peak sensitivity range in the adult rat auditory system is 8±16 kHz [63] and effective priming and testing stimuli include pure tones or a broad frequency band (e.g. doorbell, ®rebell, or white noise) of suf®cient intensity [107,110,119]. Lastly, the duration of the priming stimulus can in¯uence the percentage of subjects that become susceptible [59,107,129]. Generally, a minimum exposure of 30 s is required for AGS induction; a very long exposure period, such as 12 min, may actually reduce the likelihood of successful AGS induction [107], possibly due to deafness. The optimal priming day varies across rodent strains, from PND 13 in the Sprague±Dawley rat [103] and PND

K.C. Ross, J.R. Coleman / Neuroscience and Biobehavioral Reviews 24 (2000) 639±653

4. Anatomical and neurochemical substrates of audiogenic seizures

Table 3 Priming induction parameters by rodent strain Strain Rat Wistar Sprague± Dawley Long± Evans Mouse SJL C57 BALB/c a b c

643

Day Primed a

Intensity b (dB SPL)

Day Tested c

Reference

14 13±15

125 125

28 32±36

[107] [103]

18

125

32

[119]

21 16 16 21

102 127 112 131

23 20 21 28

[110] [129] [130] [14]

Day Primed: day of priming reported for inducing AGS susceptibility. Intensity: stimulus intensity used for priming and testing. Day Tested: day of testing reported for inducing AGS susceptibility.

18 in the Long±Evans rat [119] to PND 21 in the SJL mouse [109] and BALB/c mouse; Ref. [14], see Table 3. The optimal priming interval corresponds roughly to the period after the external meatus of the rodent ear opens and the middle ear becomes clear of mesenchyme [3,10]. The priming days listed in Table 3 are not the only days in which intense sound exposure can produce AGS behaviors, but are associated with the highest percentage of permanent AGS susceptibility. The range of effective priming days between and within strains suggests that the ªwindow of opportunityº for successful AGS induction also is dependent upon the testing day and stimulus intensity for both priming and testing. The initial day of testing for AGS behavior is a critical variable for inducing AGS susceptibility in resistant strains. The reason(s) for a critical testing window are not well understood. Table 3 shows a wide distribution of reported optimal testing days, the earliest being PND 20 for primed C57BL/6J mice [129] and the latest being between PND 32 and PND 36 for primed Wistar rats [103,107] and Long± Evans rats [119]. The testing days are strain-dependent, and are usually later for rats than mice. For certain strains, the optimal testing day is within a range of days in which susceptibility can be induced; for example, in Long± Evans rats, the optimal testing day is 32, but AGS susceptibility may develop in a few subjects tested on day 28 or 30 [119]. The average stimulus intensity required for successful AGS induction in primed strains is 121 dB SPL (range 102±131 dB SPL; Table 3), which are intensities that may damage the inner ear of mammals with prolonged exposure. One of the prevailing hypotheses regarding AGS susceptibility is that short-term hearing loss is necessary during maturation of the auditory system so that the subject will be hypersensitive (and hyper-responsive) to very intense stimulation during the testing phase of AGS [14,86, 87,127,128]; see next section.

4.1. 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 to intense acoustic stimulation, where mild hearing loss may account for later hyper-responsiveness to suprathreshold stimulation. The cochlea is only partially protected from over-stimulation by an intense acoustic stimulus; the muscles of the middle ear may contract re¯exively in response to loud sound [15]. Therefore, it is relatively easy to induce damage in the cochlea with intense acoustic stimulation. In human adults, 8 h of exposure to 90 dB noise is considered hazardous to hearing; at 125 dB, among the highest AGS priming intensities used (Table 3), exposure to about 4 min in humans is considered harmful [80]. The outer hair cells (OHCs) of cochlea provide mechanical power to increase the sensitivity of inner hair cells (IHCs); Refs. [31,151] and both are particularly sensitive to intense sound. Exposing normal guinea pigs to a 10 kHz tone at 115 dB SPL for 30 min results in severe loss of OHCs, and bent, disorganized IHCs [15]. Shortening the duration of the sound exposure or reducing the intensity of the stimulus results in less severe damage, but in general the IHCs are more vulnerable to damage than the OHCs [15]. These ®ndings imply that intense acoustic stimulation can produce cochlear damage that accompanies AGS susceptibility. The period in which this exposure can induce susceptibility in primed strains (Table 3) or elicit seizure activity in genetically-prone strains is linked to cochlear development. Anatomical studies in Sprague±Dawley and Lewis rats reveal that the three rows of OHCs of the basal region of the cochlea reach adult widths around PND 10, while in the apical region, OHCs reach adult widths around PND 16 [10]. Furthermore, the density of the single row of IHCs peaks around PND 15 [10] after ®nal growth of IHCs [94]. In rats, a startle response can be elicited as early as PND 9±12 [28], while the opening of outer ear occurs at PND 12±14, see Ref. [22]. This is accompanied by an increase in the frequency range of responses at the round window which reaches adult sensitivity at PND 16±20 [28], when wave I of the auditory brainstem response is also consistently observed to widespread tonal stimulation [3]. Coupled with behavioral observations on AGS induction, these data suggest a developmental period in which cochlear anatomy and function make it especially vulnerable to

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K.C. Ross, J.R. Coleman / Neuroscience and Biobehavioral Reviews 24 (2000) 639±653

over-stimulation. Neurotransmitter function at the cochlear level during this particularly sensitive period may play a vital role. GABA is implicated as a neurotransmitter for both efferent projections from the cochlea [4], and input to the cochlea, originating in part from the medial superior olive [146]. Glutamate is implicated in IHC afferent activity [74,77,81], and its action may be modi®ed by dopamine [98]. During postnatal development in rats, the receptors of two analogs of glutamate, NMDA and AMPA, are transiently or overly expressed. There is an upregulation of NMDA receptor subunit NR1 between PND 5 and 10 in OHCs and between PND 5 and 18 in IHCs [74]. There is also transient expression of AMPA receptor subunits GluR3 and GluR4 in the cochlea during the ®rst two postnatal weeks that is undetectable in adult subjects [81]. Differentiation of afferent GABA ®bers in the cochlea is later than in other structures and may not mature until the end of the ®rst postnatal month in mouse [146], although there is con¯icting evidence in rat [88]. These ®ndings indicate possible substrates of cochlear hyper-responsivity during the critical period: a transient upregulation of several types of glutamate receptors that increases excitatory transmission from the hair cells during acoustic over-stimulation, and a reduction of GABA-mediated inhibition at the cochlear level. Furthermore, if cochlear GABA projections from higher auditory brainstem areas such as the superior olive are not fully mature during the critical period, modulatory mechanisms may be less effective. The interaction of anatomical, neurochemical and physiological factors during a particular period in postnatal rodent development may explain the occurrence of cochlear anatomical and functional abnormalities that accompany AGS susceptibility. Investigation of cochleae from moderately audiogenic seizure-prone GEPR-3 subjects revealed missing IHCs and irregular rows of OHCs at the electron microscopy level [101]. However, subjects were tested for AGS to insure susceptibility before histology was performed, leaving the possibility that the cochlear abnormalities observed resulted from AGS testing and were not innate morphological abnormalities that accounted for seizure susceptibility. In rats primed for AGS, there was little evidence of cochlear anomalies (measured as hair cell losses) at the light microscopy level compared to unprimed controls, even after seizure testing [102]. Thus, if signi®cant cochlear damage occurs during priming, it may only be detectable at the electron microscopy level. Functional abnormalities at the cochlear level have been noted in genetically susceptible and primed rodent strains. Saunders et al. [127] observed increased cochlear microphonic thresholds in primed BALB/c mice after one week only between 3 and 25 kHz (maximal 25 dB elevation at 17 kHz) [127]. In the primed Long±Evans rat, there is a marginal elevation of the auditory brainstem response threshold; 12 dB at 40 kHz, Ref. [25]. In LP/J mice, auditory nerve thresholds for 16±32 kHz stimulation increased substantially between PND 24 and 32 (40±45 dB difference),

which coincides with maximal AGS susceptibility in this strain [63]. Lastly, auditory brainstem response (ABR) thresholds are elevated by 32.5 dB SPL in GEPR-9 rats, 55 dB in GEPR-3 rats, and wave I latencies of the ABR are increased [42]. These data suggest that some hearing de®cits occur during maturation and adulthood after priming, but hearing loss is more profound in genetically prone AGS subjects. The hypothesis that cochlear damage can induce susceptibility is supported by the induction of AGS susceptibility in Wistar rats by systemic injections of the ototoxicant kanamycin, especially at PND 9±12 [76,106]. Given the correlation of elevated hearing threshold and abnormal cochlear function in AGS-susceptible rodents, it is likely that mild hearing attenuation accounts for hyperresponsivity to intense sound stimulation [127,128]. Hearing attenuation is most likely to induce AGS susceptibility if it occurs during postnatal maturation of the auditory system (as in GEPRs), or during a critical period within postnatal auditory system development (as in primed strains). The attenuation need not result from intense sound exposure; AGS susceptibility can be induced via bilateral tympanic membrane destruction in BALB/c mice at PND 14 or 21 [14] and PND 19±21 [60] or via earplugs inserted on PND 17 in C57B/6J mice [86,87]. The attenuation can also be mild: ABR thresholds are only marginally elevated in the AGS-prone Long±Evans rat [25]. In fact, AGS susceptibility and severity can actually decrease with longer exposure times during priming [107] or with more profound hearing threshold increases [42]. The critical variable for inducing AGS susceptibility in rodents is a restriction of auditory input during the postnatal development of the auditory system, although this aspect can be challenged by successful AGS induction with priming in adult BALB/c mice [58]. 4.2. Central AGS afferent pathway Compromised auditory input during a sensitive period in postnatal development presumably has consequences throughout the auditory brainstem. Higher click evoked potential amplitudes were recorded in the primed BALB/c mouse cochlear nucleus at stimulus intensities above 95 dB, but lower relative amplitudes below this intensity [128]. A recent examination of the ABR of the primed Long±Evans rat by Coleman et al. [25] con®rms this ®nding at several levels of the auditory neuraxis. Primed AGS-susceptible animals recorded at 4±6 months showed response latencies comparable to control subjects at 50 dB using 8 and 40 kHz tonal stimuli; however, at higher intensities primed subjects displayed shorter wave Ia±VI latencies, despite marginal response threshold increases in these animals [25]. Reductions in interpeak latencies between waves Ia±V to 8 kHz 90 dB stimulation for seizure-prone subjects are accentuated at wave IV±V, which likely involves the inferior colliculus [25]. Therefore, the effects of priming during a sensitive period of development may accelerate evoked

K.C. Ross, J.R. Coleman / Neuroscience and Biobehavioral Reviews 24 (2000) 639±653

responses at different levels of the central auditory pathway in adult subjects. Investigation of lower auditory brainstem structures in audiogenic seizure-susceptible subjects are rare, possibly because of their proximity to life-sustaining structures such as the medulla [7]. Faingold et al. [40] found reduced AGS activity in GEPR-9s following bilateral microinjection of NMDA receptor antagonist APH into the ventral and dorsal cochlear nuclei and superior olivary complex, which indicates a glutaminergic contribution of lower auditory brainstem structures to AGS progression through the auditory pathway. 4.3. Anatomical, electrophysiological, and immunochemical studies of the inferior colliculus in AGS models The inferior colliculus (IC) has been implicated as a critical structure in audiogenic seizure susceptibility. Based on cell types and architecture, the IC is usually divided into the central nucleus (CNIC), dorsal cortex (DCIC) and external cortex (ECIC); Refs. [23,44]; see Fig. 2A. In rat, the CNIC is bordered rostrally, laterally, and ventrally by the ECIC, and caudally and dorsally by the DCIC. Functionally, the IC participates in the coding of auditory stimulus characteristics, such as frequency and binaural processing [34,46,71]. Bilateral lesions of IC abolish AGS permanently [55,72,144,147], especially if the lesion damages the CNIC [147]. Marginal AGS attenuation (i.e. wild running only) results from IC lesions [120], particularly lesions that damages ECIC [147]. Furthermore, unilateral IC implantation of embryonic caudal tectum in susceptible Long-Evans rats results in additional AGS attenuation compared to unilateral lesions alone [120,123]. In contrast to the effects of damage or restitution in the IC, Willott and Lu found no reduction of AGS behaviors after lesions of the medial geniculate body of the thalamus [147]. Based on the strong relationship between IC structure and function and AGS susceptibility, research on the anatomical substrates of AGS has focused on the IC, where electrophysiological hyper-responsivity to intense sound stimulation can occur. Evoked IC response amplitudes were reduced in primed BALB/c mice with stimulation intensities between 60 and 87 dB, but increased with intensities up to 110 dB [128]. Recent data from auditory brainstem response recordings in AGS-prone Long±Evans rats also suggests hyper-responsivity to incoming stimulation beyond some critical intensity level: waves IV±V showed reduced ABR latencies at 70 and 90 dB compared to controls [25]. Direct electrical stimulation of IC cortex, even as early as ®ve days of age prior to hearing onset, elicits after-discharge-like activity, as well as wild running, forelimb padding, and hindlimb treading behaviors [85]. Studies using Fos immunochemistry [93] have con®rmed enhanced activity within the IC, particularly in the DCIC and ECIC, in both developmentally primed [76,104,137]

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and genetically susceptible subjects [19,78,135,136] exposed to seizure-inducing stimulus intensities. Fos patterns in the IC of adult primed Wistar rats after tonal stimulation were similar to those of untreated subjects at PND 14 [104,105], suggesting that the transient input de®cit induced by priming sustained immature IC patterns. Normal maturation of the IC from regular acoustic input is characterized by distinct tonotopic bands in the adult IC [16,21,34,46]. These bands are dense and more diffusely distributed in subjects primed during development [104,137], or absent in genetically susceptible subjects [19] in which a normal auditory system maturational process is not experienced [42]. The results from IC studies offer compelling evidence that abnormal IC reactivity may occur in response to supra-threshold stimulation. At the neuronal level, an increased percentage of CNIC neurons in GEPRs displayed an onset-offset response (a peak at the beginning and end of the stimulation) at high stimulus intensities (80 dB or higher) compared to controls [41]. It has been suggested that the offset response, observed signi®cantly less in controls, may be a phenomenon similar to an afterdischarge, and may represent a lack of inhibition in the CNIC [41]. There is also an increase in both the number of action potentials ®red by GEPR ECIC neurons in response to stimulation 10 dB above threshold compared to seizure-resistant controls, and in the percentage of GEPR neurons displaying sustained ®ring [12]. Lastly, more GEPR-9 DCIC in vitro action potentials are recorded to supra-threshold current intensities than in controls [79]. Supra-threshold activation of the CNIC, which exclusively receives auditory information [23] provides critical projections to the remaining cortex of IC, which may functionally innervate motor circuits that subserve AGS behaviors (Fig. 2A). Activation of the DCIC may contribute to seizure propagation through its known connections with structures such as the ECIC, which also receives a large projection from the ipsilateral CNIC [11,23]. There are interconnections between ECIC and the deep layers of the superior colliculus (DLSC) [23,56], where integration of multi-modal sensory cues and orienting behaviors occurs [100] and there is output to motor circuits; see Ref. [139] for review. The ECIC also projects directly to regions of the reticular formation (RF) including the pontine nucleus, the ventrolateral tegmental nucleus, the gigantocellular reticular nucleus, and the lateral paragigantocellular nucleus; DCIC shows more restricted projections [11]. 4.4. Pharmacological studies of the inferior colliculus in AGS models Audiogenic seizure-susceptible subjects display clear functional abnormalities in the IC. Additional work using primarily genetically AGS-susceptible subjects has examined IC neurotransmitter anomalies and manipulations for the amino acid neurotransmitters glutamate and GABA

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Fig. 2. Neuroanatomical structures implicated in audiogenic seizure propagation. (A) Subdivisions of the inferior colliculus (IC) and probable role in AGS. CNIC ˆ central nucleus of the inferior colliculus. ECIC ˆ external cortex of the inferior colliculus. DCIC ˆ dorsal cortex of the inferior colliculus. (B) AGS efferent pathways beyond ECIC. Solid lines indicate direct AGS efferent pathway, dashed lines indicated modulatory AGS efferent pathway. IC ˆ inferior colliculus. SC ˆ superior colliculus. NSTR ˆ neostriatum. SN ˆ substantia nigra. RF ˆ reticular formation. CB ˆ cerebellum. SPC ˆ spinal cord.

and other neurotransmitter systems which play a role in audiogenic seizure progression (Table 4). Glutamate is implicated in the aberrant processing of acoustic information in the inferior colliculus that may lead to audiogenic seizures. The IC pathway contains a selected glutaminergic projection to the RF [126] that may provide a substrate for propagation of AGS. HPLC measurement in the CNIC of GEPR-9 subjects reveals comparatively high levels of glutamate [115], and AGSsusceptible Swiss mice show increased in situ hybridization labeling of NMDA receptor subtypes NR1 and NR2C [84]. The NR2C receptor subunit observed in this study is not normally identi®ed in the IC, and was proposed to induce sustained glutaminergic activity in combination with the NR1 subunit [84]. Following NMDA microinjections into CNIC, wild running and clonic behaviors were observed in nonsusceptible rats: 35% displayed seizures only in response to sound, while the remaining 65% had both spontaneous and sound-induced seizures [89]. Injections of APH into the CNIC produced a marked reduction in AGS severity in GEPR-9s [40]. CNIC or DCIC microinjections of NMDA induced some aspects of AGS-like activity before sound stimulation (jumping, falling) in AGS-resistant rats; CNIC

injections resulted in full-blown AGS-like behavior (wild running, convulsions) during sound stimulation [141]. AGS severity was decreased by injections of NMDA antagonist AP7 into the CNIC, but not DCIC [141]. From these studies, it can be concluded that the glutamate system within IC plays a crucial role in audiogenic seizure activity. Increasing glutaminergic transmission intensi®es AGS and decreasing glutamate transmission reduces AGS severity or abolishes it, which is consistent with glutamate's hypothesized function as an excitatory amino acid transmitter. Manipulating the glutamate system is also effective in producing seizures in other models of generalized tonic± clonic epilepsy, e.g. Refs. [29,82]. There is extensive empirical data to support the assumption that GABA, the major inhibitory neurotransmitter of the brain, is also directly implicated in AGS activity. Focal IC microinjections of GABA-A agonist muscimol [8] or GABA-B agonist baclofen [39] blocked seizure activity in GEPR-9s [39], in contrast to injections of noradrenergic agonists [8]. IC microinjections of the GABA transaminase inhibitor gabaculine, which blocks the degradation of GABA, also reduced AGS severity [39]. Within the IC, more GAD-positive somata were identi®ed in all three IC subnuclei of GEPR-9 rats compared to Sprague± Dawley controls [118] and increased GAD mRNA expression was noted in the CNIC and ECIC of GEPR-9s compared to controls [116]. Analysis using HPLC has revealed increased CNIC GABA levels in GEPR-9 subjects [115]. These results are intriguing, because it appears that application of GABA-promoting agents, especially to the IC, can be effective in reducing AGS severity, but intrinsic GABAergic inhibition within the IC appears to be compromised, even with higher numbers of GAD-positive neurons and higher GABA levels. For example, the iontophoretic dose of GABA required to suppress ®ring of CNIC neurons during acoustic stimulation is higher in GEPRs than in normal subjects [38]. In seizure-resistant rats, manipulations of the GABA system impact AGS susceptibility. IC injections of the GABA-A antagonist bicuculline in non-susceptible Sprague±Dawley rats produce sound-induced seizures, including wild running and occasionally clonus [89]. Likewise, AGS-like behaviors in resistant Wistar rats are elicited after bicuculline injections into CNIC [140]. The critical role of GABA in IC responsivity is supported by increased IC auditory evoked potential (AEP) amplitudes after focal microinjections of bicuculline and decreased AEP amplitudes following microinjections of THIP, a GABA-A receptor agonist [2]. Together, the electrophysiological, immunochemical, and pharmacological ®ndings in the IC of AGS-susceptible or comparably-treated (i.e. acoustically deprived) subjects are indicative of hyper-responsivity to sound in these subjects. Glutamate and its receptors may be overly abundant in the IC, contributing to increased responsivity to afferent signals from lower auditory

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Table 4 Pharmacology of audiogenic seizures (NP, non-protective against AGS; P, protective against AGS) NT

Putative role

Site

Strain

Reference

Glutamate

NP NP NP NP

Cochlea Superior olive Cochlear nucleus IC

Rat GEPR GEPR Rat Rat

[77] [40] [40] [89] [141]

GABA

P P

Cochlea IC

Guinea pig GEPR GEPR

[4] [38] [39]

Dopamine

P P

Cochlea Systemic

Guinea pig GEPR Mouse

[98] [70] [30]

Serotonin

P

Systemic

Mouse GEPR

[138] [148]

Norepinephrine

P?

Systemic

GEPR

[5]

brainstem structures, which already would display abnormally ampli®ed responses to supra-threshold stimulation [25,127]. The result would be increased electrical activity [128] and increased activation of IC neurons [104,137]. Conversely, GABA, while certainly abundant in the IC (at least in GEPRs), may be less effective. Without GABAergic inhibition, especially in a hyperexcitable IC, a potentially seizure-producing discharge could result. 4.5. AGS efferent pathway The substrates for the AGS efferent pathways have gradually become better understood. The AGS efferent pathway may divide at the level of the ECIC into direct and modulatory courses, both of which terminate in the reticular formation (RF) as the last likely requisite supra-spinal structure mediating AGS expression. In several brainstem models of seizures, the RF is involved in the efferent seizure pathway, as lesions of RF subnuclei attenuate tonic and clonic seizure components [6]. In GEPR-9 subjects RF glutamate increases during seizures [13], and APH injections into the mesencephalic and caudal pontine RF reduce incidence of AGS [90]. Recently, the subdivision of the lateral parabrachial area has been identi®ed as an area of high Fos induction following generalized tonic seizures induced by sound or electroshock [35]. The ECIC has prominent descending projections to several areas of the reticular formation [11], including the pontine nucleus, the ventrolateral tegmental nucleus, the gigantocellular reticular nucleus, and the lateral paragigantocellular nucleus, which may subserve the direct AGS efferent pathway. The projection from IC to the RF may be glutaminergic in nature; injections of d-[ 3H]aspartate into the CNIC of chinchillas revealed anterograde labeling

in the dorsolateral pontine nucleus [126]. The intercollicular zone, corresponding to the most rostral part of the ECIC, also projects to reticular nuclei such as the caudal pontine reticular nuclei and gigantocellular reticular nucleus [11]. The proposed AGS direct pathway from IC to reticular structures may be modi®ed at the collicular or reticular level by a number of subcortical structures (Fig. 2B). For example, in the periaqueductal gray (PAG) of GEPR subjects, neurons exhibit a tonic ®ring pattern just prior to the onset of tonic convulsions [96]. AGS susceptibility is suppressed in GEPR-9s by blockade of NMDA receptors (AP7) or activation of GABA-A receptors (THIP) in the PAG [97]. Administration of opiate peptide receptor antagonist naloxone into the PAG resulted in AGS suppression [97]. These data suggest that PAG glutamate, GABAergic, and opioid mechanisms modulate AGS propagation. Another important modulatory structure in the AGS network is the superior colliculus (SC). The role of SC in AGS progression is supported by incomplete attenuation of AGS by midcollicular knife cuts [142] or SC lesions [147] and the presence of non-speci®c (i.e. not just audiogenic) seizure activity following SC manipulations [89,142]. There are direct descending projections from the SC to the pontine reticular formation and pontomedullary reticular formation [108] and to the medullary parvicellular reticular formation and regions around the motor trigeminal nucleus [150]. The intercollicular zone also has descending projections to subdivisions of the pontine reticular formation, including pars caudalis and pars oralis, and when stimulated, the intercollicular zone is anticonvulsant in the maximal electroshock (MES) model of epilepsy [133]. Focal microinjections of picrotoxin (a noncompetitive GABA-A receptor antagonist) into the deep layers of superior colliculus (DLSC) in rats produce explosive wild running behavior in two-thirds of subjects [27]. In the

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audiogenic seizure model, lesions to DLSC reduce the incidence of tonic±clonic components of AGS in DBA/2 mice, while wild running perseveres [147]. Deep midcollicular knife cuts (between IC and SC) attenuates most AGS behaviors in seizure-prone subjects and in seizure-resistant subjects with dose-limited CNIC bicuculline injections [142]. Focal DLSC microinjection of either bicuculline or NMDA into normal rats produces spontaneous seizure activity, but AGS activity is primarily produced by NMDA injections [89]. Though the SC is implicated as a requisite structure for AGS [49,56], lesion and transection data con®rm that the SC is not an obligatory relay for seizure propagation. In addition to these AGS anatomical substrates which have been previously discussed [117], recent experimental ®ndings further implicate the substantia nigra (SN) in AGS modulation. Garcia-Cairasco et al. [55] found that unilateral SN lesions increase AGS severity in initially resistant Wistar rats. SN injections of clobazam block AGS-like seizures induced by focal microinjections of bicuculline into the IC of resistant Wistar rats, but not WAR rats [140]. APH microinjection into the pars reticulata (SNPR) or pars compacta (SNPC) abolish AGS in GEPR-9s [90], although there is an increase in behaviors such as rotating and stereotypic snif®ng. The ®nding that SNPR and SNPL (pars lateralis) project to IC [99] and SC [1] is consistent with the assertion that the SN generally regulates efferent seizure pathways [49]. Modulation of SC by SN is in turn governed in part by activity in the neostriatum, where dopamine activity increases GABAergic release along the SN±SC pathway. Increasing GABA activity in the SN±SC pathway is believed to be pro-convulsant [27,48] because the resulting reduction of GABAergic output of SC onto motor structures such as the reticular formation may produce a seizure state. This is supported by observations of wild running behavior with a subconvulsive dose of picrotoxin into rat SC following focal microinjections of the dopamine agonist apomorphine into neostriatum [27]. This behavior could be blocked with a focal neostriatal injection of haloperidol, but not in subjects receiving a supra-threshold dose of picrotoxin in the SC. Therefore, it can be concluded that SN and neostriatum in¯uence the activity of SC and RF in the AGS model, which is largely glutaminergic and GABAergic in nature. 4.6. Associated neural changes in AGS-susceptible subjects While not critically involved in the AGS efferent pathway [7,9,52,54], several researchers have noted several neural changes, especially a recruitment of forebrain structures during the AGS response [57], that can occur with repeated seizure testing (i.e. ªkindledº audiogenic seizures). In the AGS-susceptible Wistar rat, repeated auditory exposure results in further development of tonic±clonic seizures and an associated appearance of cortical paroxysmal

discharges [73,83]. Some research has suggested that cortical activation in AGS progression may require increased activity of the medial geniculate nucleus [95] and amygdala [66,67]. Recently, forebrain progression in GEPR and Wistar strains was found using Fos immunochemistry [19,136]. Of particular interest is the sequence of Fos expression in kindled rats from the auditory brainstem to amygdala and perirhinal cortex, then to frontoparietal cortex, and ®nally hippocampus and entorhinal area [136]. Additional evidence for neural transfer comes from in vitro kindling studies using hippocampal slices from AGS-primed [121] or genetically AGS-susceptible subjects [132]. Slices from non-tested subjects show reduced kindled activity, which may be an early forebrain protective measure from mechanisms leading to brainstem seizures. However, there is increased in vitro hippocampal excitability in slices from GEPR-9s exposed to several AGS behavioral tests [36]. Therefore, neural transfer from auditory brainstem to hippocampus after repeated AGS testing may follow a period of decreased excitability. 4.7. AGS and monoamine system investigations Administration of pharmacological agents that affect monoamine neurotransmitter systems has yielded additional insight into possible neurochemical in¯uences on AGS (see Table 4). Several pieces of evidence support the involvement of dopamine and norepinephrine in the AGS response. For example, injection of Ro 4-1284 (benzoquinolizine), which depletes brain norepinephrine (NE) and dopamine (DA), results in a marked increase in severity of seizure activity in GEPR-3s [70]. Depletion of DA levels by aMPT (l-a-methyl-p-tyrosine) [70] or alteration of NE levels (decrease in cortex and spinal cord and increase in pons and medulla) by 6-OHDA [5] in GEPRs also results in increased seizure severity. Furthermore, injections of l-DOPA suppress AGS in DBA/2J mice with accompanying increases in brain levels of NE and DA [30]. However, pretreatment with DBH inhibitor dethyldithiocarbamate also attenuates AGS, with an increase in DA but not NE levels [30]. The indolamine serotonin (5-HT) is also implicated in AGS progression. Injections of the precursor 5-HTP attenuate AGS in DBA/2J mice [138] and reduced brain 5-HT levels at night are associated with increased AGS susceptibility in DBA/2J, C57BL/6J, and hybrid mice [131]. Reduced AGS activity in GEPR-9s has been observed following combined administration of ¯uoxetine (selective 5-HT reuptake inhibitor) and 5-HTP [148], or sertraline, a highly selective 5-HT uptake inhibitor [149]. These data suggest a protective effect of monoamine neurotransmitters against AGS when administered exogenously. Recently, in vitro studies have further elucidated structural abnormalities within GEPR locus coeruleus (LC) that may play a role in the AGS response. Reduced neurite branching in norepinephrine neurons in culture was

K.C. Ross, J.R. Coleman / Neuroscience and Biobehavioral Reviews 24 (2000) 639±653

demonstrated in GEPR-3 [20] and GEPR-9 [125] LC tissue compared to controls, suggesting a developmental de®ciency in norepinephrine ®bers in the brainstem of seizure-prone animals. 5. 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 from 5-HT-depleting injections of DHT display less severe seizure symptoms following implantation of fetal raphe tissue [17]; these effects were sustained for at least three months. Such ®ndings are consistent with the effectiveness of implanting fetal caudal tectum directly into the IC of AGS-susceptible Long±Evans rats, which reduces seizure severity to sub-clonic levels [24,123]. Since the IC contains a GABA-rich population [118], it is likely that tectal grafts are able to ameliorate seizure symptoms by a GABAergic mechanism. This is supported by recent observations of reduced seizure symptoms following implantation of immortalized rat fetal striatal cells engineered to express GAD67 into the IC of AGS subjects [122]; see Ref. [61]. These results demonstrate the potential effectiveness of neural grafting for reducing seizure susceptibility and severity. 6. 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 study of synaptic characteristics of relevant neuron populations in the subdivisions of the inferior colliculus, as well as in modulatory structures such as superior colliculus and substantia nigra, will lead to a more precise understanding of underlying mechanisms of these hyperexcitable circuits. Additional work using grafted tissue, including special cell populations such as genetically modi®ed cells for GAD production or manipulation of intrinsic neuron populations will provide opportunities for the study of altered neural substrates and neurochemical features which may modulate the exagger-

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