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C L Faingold

Publications and source records attributed to C L Faingold.

At least 19 recordsLinked to original sources
PubMed2003

Neurons in the periaqueductal gray are critically involved in the neuronal network for audiogenic seizures during ethanol withdrawal.

The periaqueductal gray (PAG) is implicated in the network subserving audiogenic seizures (AGS). AGS are seen during ethanol withdrawal (ETX), and the present study examined effects of focal NMDA receptor blockade in PAG during ETX and PAG neuronal firing changes associated with ETX. Bilateral cannulae or microwire electrodes were chronically implanted into PAG. Ethanol was administered intragastrically at 8-h intervals for 4 days, resulting in AGS susceptibility during ETX. Microinjection of a competitive NMDA receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7) (2 and 5 but not 1 nmol/side), into the PAG suppressed AGS, in part, reversibly. In microwire experiments spontaneous and acoustically evoked PAG neuronal responses in behaving rats were reduced significantly 1 h after initial administration of ethanol. During ETX, when the animals were susceptible to AGS, significant increases in spontaneous and acoustically evoked PAG neuronal firing occurred. PAG neurons exhibited burst firing 2-4 s prior to the tonic-clonic phase of AGS and tonic repetitive firing during this seizure phase, which ceased during post-ictal depression. Increased NMDA receptor function in PAG may be important to the aberrant PAG neuronal firing in AGS, since previous studies observed upregulation of NMDA receptors during ETX, and the present study observed that focal microinjection of a NMDA antagonist into PAG blocked AGS.

2-Amino-5-phosphonovalerate↗
PubMed2001

Neurons in the deep layers of superior colliculus are a requisite component of the neuronal network for seizures during ethanol withdrawal.

Ethanol withdrawal (ETX) in ethanol-dependent animals and humans often results in seizure susceptibility. The deep layers of superior colliculus (DLSC) are proposed to be involved in the neuronal networks of several types of seizures. In rodents, ETX results in susceptibility to audiogenic seizures (AGS), and the DLSC are implicated as a critical component of the seizure network in a genetic form of AGS. Ethanol inhibits NMDA receptors, and the binding at these receptors is increased during ETX in certain brain regions. Therefore, the effect of focal microinjection into DLSC of a competitive NMDA receptor antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7) on ETX seizures was examined. AP7 (2 and 5 nmol/side) microinjected bilaterally into DLSC suppressed AGS, supporting a critical role of the DLSC in the AGS network during ETX. DLSC neuronal firing changes in behaving rats were subsequently examined, using chronically implanted microwire electrodes. Acoustically-evoked DLSC firing was significantly suppressed during ethanol intoxication and during ETX. However, DLSC neurons began firing tonically 1-2 s before the onset of the wild running behavior of AGS. Acoustically-evoked DLSC firing was suppressed during post-ictal depression with recovery beginning as the righting reflex returned. These data support a requisite role of the DLSC in AGS during ETX. These neuronal firing changes suggest an important role of DLSC neurons in generation of the wild running phase of AGS during ETX, which may be a general pathophysiological mechanism and a critical event in the initiation of wild running, since a similar pattern was seen previously in a genetic form of AGS.

Acoustic Stimulation↗
PubMed2001

Audiogenic seizure susceptibility is induced by termination of continuous infusion of gamma-aminobutyric acid or an N-methyl-D-aspartic acid Antagonist into the inferior colliculus.

The inferior colliculus (IC) is strongly implicated in seizure initiation in a genetic form of audiogenic seizures (AGS) and in AGS observed during ethanol withdrawal (ETX). Ethanol is known to block the actions of excitatory amino acids (EAA) and enhance the actions of gamma-aminobutyric acid (GABA) in several brain areas, including the IC. The present study investigated the effects on susceptibility to AGS following withdrawal from continuous blockade of N-methyl-D-aspartic acid (NMDA) receptors or continuous activation of GABA receptors in the IC. This involved infusion of GABA (1 M) or a competitive NMDA antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 mM), at 0.25 microl/h for 7 days using an Alzet osmotic minipump. Following abrupt termination of the infusion, AGS susceptibility began at 30 min. The incidence of AGS was 38.9 and 56.3% following GABA and AP7 withdrawal, respectively. The AGS behaviors observed during withdrawal, which included wild running and bouncing clonus, were very similar to those evoked by acoustic stimuli during ETX. AGS susceptibility lasted for several hours and in 13% of animals persisted for up to 6 months. The current results support diminished GABAergic and elevated glutamatergic function in the IC as the critical mechanisms and sites for AGS initiation. The present study, coupled with previous evidence that chronic ethanol exposure reduced GABA-mediated inhibition and enhanced EAA-mediated excitation, suggests that these amino acid receptor-mediated alterations in the IC are key elements in initiating AGS during ethanol withdrawal.

2-Amino-5-phosphonovalerate↗
PubMed2001

Modulation of audiogenically kindled seizures by gamma-aminobutyric acid-related mechanisms in the amygdala.

Repetitive induction of audiogenic seizures (AGSs) ("AGS kindling") results in expansion of the AGS neuronal network from the brainstem to forebrain structures. AGSs in kindled genetically epilepsy-prone rats (GEPR-9s) exhibit a significant increase in the duration of posttonic clonus (PTC). The amygdala (AMG) does not appear to be a required network component before AGS kindling, but this structure is implicated in the seizure network after AGS kindling. gamma-Aminobutyric acid (GABA) is a major neurotransmitter in AMG, and histamine receptor activation is also reported to stimulate GABA release. The present study examined the effect on audiogenically kindled seizures of focal microinjections into the AMG of GEPR-9s. AGS kindling involved induction of 14 AGSs in GEPR-9s. Bilateral microinjection of a GABA(A) agonist, muscimol (0.3 nmol/side), into the AMG significantly reduced the duration of PTC, starting 0.5 h after drug infusion, with recovery by 24 h. Microinjection of histamine (60 nmol/side) suppressed PTC at 0.5 h, with total blockade at 24 h, but the seizure pattern did not revert to that observed before kindling until 120 h. This long duration suggests that mechanisms in addition to modulation of GABA function may be involved in the effect of histamine. The wild running and tonic components of AGS were never affected by microinjection of these agents into the AMG. These findings confirm previous work suggesting that the AMG is not a required nucleus in the AGS neuronal network before kindling. However, the AMG becomes critical in expansion of the seizure network during AGS kindling, and audiogenically kindled seizures are negatively modulated by increased GABA function.

Acoustic Stimulation↗
PubMed2000

Phenytoin administration reveals a differential role of pontine reticular formation and periaqueductal gray neurons in generation of the convulsive behaviors of audiogenic seizures.

The ventrolateral periaqueductal gray (PAG) and pontine reticular formation (PRF) are implicated in the neuronal network for audiogenic seizures (AGS). The AGS of genetically epilepsy-prone rats (GEPR-9s) culminate in tonic hindlimb extension (TE), and elevated acoustically evoked neuronal firing and burst firing, immediately preceding TE, have been observed in PAG and PRF. This study examined changes in PAG and PRF neuronal firing and behavior in GEPR-9s, following phenytoin administration. Recordings involved 16 PAG and nine PRF neurons in GEPR-9s. Phenytoin in doses (mean, 6. 3 mg/kg) that suppressed TE selectively did not consistently alter PAG neuronal firing. However, these doses of phenytoin resulted in significant (51.6% of control) suppression of PRF neuronal firing. Doses of phenytoin (mean, 8.3 mg/kg), which completely blocked AGS, significantly reduced PAG neuronal firing (64.6% of control), and more greatly suppressed PRF firing (25.8% of control). These results are consistent with a critical role for PRF neurons in generation of TE not evident for PAG. The suppression of PAG and PRF neuronal firing induced by phenytoin with complete seizure blockade is consistent with vital roles for both structures in the seizure network. The differential effects of phenytoin on structures requisite to the seizure network indicate that this experimental approach may be able to identify the most sensitive therapeutic target for anticonvulsant drugs, which could be critical to pharmacological suppression of specific seizure behaviors manifest in various types of convulsions, potentially including human epilepsy.

Action Potentials↗
PubMed2000

Modulation of audiogenic seizures by histamine and adenosine receptors in the inferior colliculus.

Susceptibility to behaviorally similar audiogenic seizures (AGS) occurs genetically and is inducible during ethanol withdrawal (ETX). Comparisons between AGS mechanisms of genetically epilepsy-prone rats (GEPR-9s) and ethanol-withdrawn rats (ETX-Rs) are yielding information about general pathophysiological mechanisms of epileptogenesis. The inferior colliculus (IC) is the AGS initiation site. Excitatory amino acid (EAA) abnormalities in the IC are implicated in AGS, and histamine and adenosine receptor activation each reduce EAA release and inhibit several seizure types. Previous studies indicate that focal infusion of an adenosine receptor agonist into the IC blocked AGS in GEPR-9s, but the effects of adenosine receptor activation in the IC on AGS in ETX-Rs are unknown. The effects of histamine receptor activation on either form of AGS are also unexamined. The present study evaluated effects of histamine or a nonselective adenosine A(1) agonist, 2-chloroadenosine, on AGS by focal microinjection into the IC. Ethanol dependence and AGS susceptibility were induced in normal rats by intragastric ethanol. Histamine (40 or 60 nmol/side) significantly reduced AGS in GEPR-9s, but histamine in doses up to 120 nmol/side did not affect AGS in ETX-Rs. 2-Chloroadenosine (5 or 10 nmol/side) did not affect AGS in ETX-Rs, despite the effectiveness of lower doses of this agent in GEPR-9s reported previously. Thus, histamine and adenosine receptors in the IC modulate AGS of GEPR-9s, but do not modulate ETX-induced AGS. The reasons for this difference may involve the chronicity of AGS susceptibility in GEPR-9s, which may lead to more extensive neuromodulation as compensatory mechanisms to limit the seizures compared to the acute AGS of ETX-Rs.

2-Chloroadenosine↗
PubMed1999

Neurons in the deep layers of superior colliculus play a critical role in the neuronal network for audiogenic seizures: mechanisms for production of wild running behavior.

Recent investigations suggest that the deep layers of superior colliculus (DLSC) play a role in the neuronal network for audiogenic seizures (AGS). The present study examined DLSC neuronal firing and convulsive behavior simultaneously in freely-moving genetically epilepsy-prone rats (GEPR-9s) using chronically implanted microwire electrodes. An abrupt onset of acoustically-evoked firing at approximately 80-90 dB was observed in DLSC neurons of GEPR-9s, which was significantly above the normal threshold. DLSC neurons began to exhibit rapid tonic burst firing 1-2 s prior to the onset of the wild running behavior at the beginning of AGS. As the tonic phase of the seizure began, DLSC firing ceased, and only returned towards normal following post-ictal depression. These neuronal mechanisms may be relevant to other seizure models in which the DLSC is implicated. The temporal pattern of neuronal firing during AGS is specific to DLSC and differs markedly from those observed elsewhere in the AGS neuronal network. The temporal firing pattern suggests that the DLSC plays a primary role in the generation of the wild running phase of AGS. Previous studies indicate that the inferior colliculus is dominant during AGS initiation, and the pontine reticular formation is dominant during the tonic extension phase of AGS. Taken together these data suggest that the neurons in the neuronal network undergo a dominance shift as each specific convulsive behavior of AGS is elaborated.

Acoustic Stimulation↗
PubMed1999

Differential roles in the neuronal network for audiogenic seizures are observed among the inferior colliculus subnuclei and the amygdala.

The inferior colliculus (IC) is established as the initiation site within the neuronal network for audiogenic seizures (AGS), but the relative importance of the IC subnuclei in AGS is controversial. The lateral and basolateral subdivisions of the amygdala are implicated in the expansion of the AGS network that occurs during AGS kindling. However, the role of the amygdala in the AGS network in nonkindled AGS is unknown. NMDA receptors are implicated in modulation of AGS and in neurotransmission in both the IC and amygdala. Therefore, changes in AGS severity in genetically epilepsy-prone rats (GEPR-9s) were examined after bilateral focal microinjection into IC subnuclei or lateral/basolateral subdivisions of the amygdala of a competitive NMDA receptor antagonist, 3-((+)-2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP). Blockade of AGS in IC central nucleus (ICc) and external cortex (ICx) was observed at identical doses of CPP, but these doses were ineffective in IC dorsal cortex (ICd). Microinjection of CPP into the amygdala did not produce significant changes in AGS severity except at doses 20 times those effective in IC. The latter data contrast with the anticonvulsant effects of amygdala microinjections on seizure severity in kindled AGS reported previously. The present data in concord with neuronal recording studies of these nuclei suggest that the ICc is the most critical site in AGS initiation, the ICx in propagation, and that the ICd plays a lesser role in the AGS network. The amygdala does not appear to play a requisite role in the neuronal network for AGS in animals that have not been subjected to AGS kindling.

Acoustic Stimulation↗
PubMed1999

Synaptic response patterns of neurons in the cortex of rat inferior colliculus.

The present study examined synaptic potentials of neurons in inferior colliculus (IC) cortex slice and the roles of GABA and glutamate receptors in generating these potentials. Multipolar (82%) and elongated (18%) cells were observed with intracellular biocytin staining. Electrical stimulation of the IC commissure (CoIC) elicited only inhibitory postsynaptic potentials (IPSPs) (10% of cells), only excitatory postsynaptic potentials (EPSPs) (51%), or both (38%). IPSPs were elicited at lower thresholds and shorter latencies than EPSPs (mean: 1.6+/-1.2 ms) and IPSPs were observed in all neurons following membrane depolarization. Short-latency EPSPs were blocked by non-NMDA receptor antagonists, and longer-latency EPSPs were blocked by NMDA antagonists. CoIC stimulation evoked short-latency IPSPs (mean: 0.55+/-0.33 ms) in 48% of neurons, and the IPSPs persisted despite glutamate receptor blockade, which implies monosynaptic inhibitory input. A GABA(A) antagonist blocked IPSPs and paired pulse inhibition of EPSPs, suggesting GABA(A) receptor mediation. A GABA(B) antagonist reduced paired pulse inhibition of IPSPs, suggesting GABA(B) receptor modulation. Thus, GABA-mediated inhibition plays a critical role in shaping synaptic responses of IC cortex neurons. Normal GABAergic function in IC has been shown to be important in acoustic coding, and reduced efficacy of GABA function in IC neurons is critical in IC pathophysiology in presbycusis, tinnitus and audiogenic seizures.

2-Amino-5-phosphonovalerate↗
PubMed1999

The periaqueductal grey is a critical site in the neuronal network for audiogenic seizures: modulation by GABA(A), NMDA and opioid receptors.

The nuclei comprising the neuronal network for audiogenic seizures (AGS) are located primarily in the brainstem. Previous studies suggested a role for the periaqueductal grey (PAG) in the AGS network. The present study evaluated this possibility in genetically-epilepsy prone rats (GEPR-9s) by examining the effects of bilateral focal microinjection of a competitive NMDA receptor antagonist (DL-2-amino-7-phosphonoheptanoic acid (AP7), 1 and 5 nmol/side), a GABA(A) agonist (gaboxedol (THIP), 10 and 15 nmol) or an opioid peptide receptor antagonist (naloxone, 5 nmol) into PAG, based on the proposed role of these receptors in PAG neurotransmission. Blockade of NMDA receptors by AP7 (both doses) or activation of GABA(A) receptors with THIP (15 nmol/side) in the PAG suppressed AGS susceptibility. Naloxone displayed a seizure-suppressant effect that was delayed and incomplete. The seizure suppressant effect of AP7 or naloxone, unlike THIP, was observed at doses that did not produce motor quiescence. These data suggest that the PAG is a requisite nucleus in the neuronal network for AGS in GEPR-9s and that GABA(A), opioid peptide and NMDA receptors in the PAG modulate AGS propagation.

2-Amino-5-phosphonovalerate↗
PubMed1999

Neuronal networks in the genetically epilepsy-prone rat.

It is now possible to develop a dynamic neuronal network model for generalized convulsive seizures because of in vivo data recently obtained in a naturally occurring epilepsy model--the genetically epilepsy-prone rats (GEPR-9s). GEPR-9s exhibit audiogenic seizures (AGS) that consist of a sequence of discrete behavioral phases (i.e., wild running, clonus-tonus, and post-ictal depression). The neuronal firing changes in most nuclei implicated in the network during each phase of AGS in behaving GEPR-9s have been examined. The inferior colliculus is critical in AGS initiation, because extensive firing increases in inferior colliculus are observed preceding seizure initiation. The deep layers of superior colliculus (DLSC) are crucial to wild running, based on the emergence of tonic firing of DLSC neurons just preceding this phase. The pontine reticular nucleus (PRF) and periaqueductal gray (PAG) are critical to the clonic-tonic phase, because tonic firing patterns appear in these neurons just prior to this phase. During post-ictal depression all areas except the PRF are quiescent. These temporal relationships suggest that each nucleus plays a specific hierarchic role in each discrete convulsive behavior. Generalized tonic-clonic seizure behavior observed in human epilepsy, in GEPR-9s, and in other seizure models is likely to involve similar neuronal network components. The neurotransmitter mechanisms subserving the abnormal neuronal responses in the GEPR-9 neuronal network involve an increased availability of glutamate and a decrease in the effectiveness of gamma-aminobutyric acid (GABA) in many brain regions. Focal modification of the effects of GABA, glutamate, norepinephrine, or serotonin also modulates the nuclei of the network differentially. Together, these data reveal the anatomic, neurotransmitter, and neurophysiologic mechanisms of the neuronal network hierarchy in GEPR-9s, which is currently the most completely developed of any generalized convulsive model. Differential effects of anticonvulsants on the AGS phases and concomitant differential modifications of neuronal firing are observed on neurons in these network nuclei. With nearly complete identification of the network nuclei, the differential effects of these anticonvulsant drugs on different aspects of neuronal firing in different brain sites indicate that this experimental approach can likely identify the most sensitive therapeutic target for these agents. This concept is potentially vital to developing the most selective treatment of different convulsive behaviors occurring in human epilepsy. The neuronal network for AGS does not require brain structures rostral to the midbrain for seizure expression. However, the forebrain is recruited into an expanded seizure network through AGS repetition ("kindling"), resulting in prolonged AGS, post-tonic clonus, and epileptiform electrographic cortical abnormalities. AGS kindling produces network expansion into medial geniculate body (MGB) and amygdala and involves neuronal firing increases in MGB.

Animals↗
PubMed1998

Comparison of neuronal response patterns in the external and central nuclei of inferior colliculus during ethanol administration and ethanol withdrawal.

Convulsive seizures during ethanol withdrawal (ETX) in rodents can be precipitated by acoustic stimulation. The inferior colliculus (IC) is strongly implicated in the neuronal network for these audiogenic seizures (AGS) in animals undergoing ETX. Previous evidence indicates that the central nucleus of IC (ICc) is important in AGS initiation in ETX, but the ICc does not project directly to motor pathways. The external nucleus of IC (ICx) receives convergent output from a broad range of ICc neurons, which is not tonotopically organized, and projects to several nuclei with major motor connections. Lesion, neuroanatomical, and stimulation experiments suggest the involvement of the ICx in the AGS network in several forms of AGS, including ETX. The present study examined ICx neuronal firing patterns in awake behaving rats during ethanol administration and during ETX to examine the role of this structure directly. ICx neuronal responses during both ethanol intoxication and ETX were significantly suppressed as compared to pre-ethanol responses. ICx neuronal responsiveness was reduced (habituated) at faster (>0.25 Hz) rates of stimulus presentation. However, immediately prior to the onset of AGS, there was an increase in ICx neuronal responses that continued into the wild running phase of AGS. This increase in neuronal responses temporally corresponded to the sustained ICc neuronal responses during ETX just prior to AGS. The enhanced ICx neuronal responsiveness may be mediated, in part, by changes in GABA and glutamate receptor regulation previously observed during ETX. The net result of these changes involves a functional reversal of response habituation normally observed in ICx neurons. These data illuminate the nature of the changes in ICx neuronal function that serves to transmit the sensory input that originates in the ICc and propagates seizure to the brainstem AGS network nuclei responsible for the convulsive motor behaviors of ETX seizures.

Acoustic Stimulation↗
PubMed1998

Ethanol and neurotransmitter interactions--from molecular to integrative effects.

There is extensive evidence that ethanol interacts with a variety of neurotransmitters. Considerable research indicates that the major actions of ethanol involve enhancement of the effects of gamma-aminobutyric acid (GABA) at GABAA receptors and blockade of the NMDA subtype of excitatory amino acid (EAA) receptor. Ethanol increases GABAA receptor-mediated inhibition, but this does not occur in all brain regions, all cell types in the same region, nor at all GABAA receptor sites on the same neuron, nor across species in the same brain region. The molecular basis for the selectivity of the action of ethanol on GaBAA receptors has been proposed to involve a combination of benzodiazepine subtype, beta 2 subunit, and a splice variant of the gamma 2 subunit, but substantial controversy on this issue currently remains. Chronic ethanol administration results in tolerance, dependence, and an ethanol withdrawal (ETX) syndrome, which are mediated, in part, by desensitization and/or down-regulation of GABAA receptors. This decrease in ethanol action may involve changes in subunit expression in selected brain areas, but these data are complex and somewhat contradictory at present. The sensitivity of NMDA receptors to ethanol block is proposed to involve the NMDAR2B subunit in certain brain regions, but this subunit does not appear to be the sole determinant of this interaction. Tolerance to ethanol results in enhanced EAA neurotransmission and NMDA receptor upregulation, which appears to involve selective increases in NMDAR2B subunit levels and other molecular changes in specific brain loci. During ETX a variety of symptoms are seen, including susceptibility to seizures. In rodents these seizures are readily triggered by sound (audiogenic seizures). The neuronal network required for these seizures is contained primarily in certain brain stem structures. Specific nuclei appear to play a hierarchical role in generating each stereotypical behavioral phases of the convulsion. Thus, the inferior colliculus acts to initiate these seizures, and a decrease in effectiveness of GABA-mediated inhibition in these neurons is a major initiation mechanism. The deep layers of superior colliculus are implicated in generation of the wild running behavior. The pontine reticular formation, substantia nigra and periaqueductal gray are implicated in generation of the tonic-clonic seizure behavior. The mechanisms involved in the recruitment of neurons within each network nucleus into the seizure circuit have been proposed to require activation of a critical mass of neurons. Achievement of critical mass may involve excess EAA-mediated synaptic neurotransmission due, in part, to upregulation as well as other phenomena, including volume (non-synaptic diffusion) neurotransmission. Effects of ETX on receptors observed in vitro may undergo amplification in vivo to allow the excess EAA action to be magnified sufficiently to produce synchronization of neuronal firing, allowing participation of the nucleus in seizure generation. GABA-mediated inhibition, which normally acts to limit excitation, is diminished in effectiveness during ETX, and further intensifies this excitation.

Animals↗
PubMed1998

Periaqueductal gray neurons exhibit increased responsiveness associated with audiogenic seizures in the genetically epilepsy-prone rat.

The ventrolateral periaqueductal gray is implicated as a component of the neuronal network for audiogenic seizure. This implication is based on immunocytochemical labeling of the proto-oncogene, c-fos, and microinjection studies in the severe substrain of genetically epilepsy-prone rats that exhibits tonic seizures. The present study examines changes in acoustically evoked neuronal responses within the periaqueductal gray in the awake and behaving genetically epilepsy-prone rat as compared to normal Sprague Dawley rats. Two populations of neuronal response were observed in the periaqueductal gray of both genetically epilepsy-prone and normal rats. Most of the neurons exhibited long latencies (>10 ms) and lower thresholds, and were more responsive to the acoustic stimulus. The remainder of the periaqueductal gray neurons exhibited short latencies (<10 ms) and higher thresholds, and exhibited minimal responsiveness to the acoustic stimulus. The mean threshold of periaqueductal gray acoustically evoked neuronal firing of short-latency neurons was significantly higher than normal in the genetically epilepsy-prone rat. The number of acoustically evoked action potentials was significantly elevated in the genetically epilepsy-prone rat, particularly at the highest acoustic intensity and at a repetition rate of 1/2 s. In the genetically epilepsy-prone rat, the number of action potentials exhibited adaptation (habituation) at 1/s as compared to 1/2 s across stimulus intensities. Habituation in normal rats was observed primarily at high intensities (95 dB sound pressure level or above). During wild running and tonic seizures in the genetically epilepsy-prone rat, periaqueductal gray neurons. which had diminished firing rates due to habituation, exhibited a tonic firing pattern. Just (1-5 s) prior to the onset of tonic convulsive behaviors, an increase in the rate of periaqueductal gray tonic firing was observed. These patterns of abnormal neuronal firing suggest that periaqueductal gray neurons may be involved in generation of the tonic seizure behavioral component of audiogenic seizure in the genetically epilepsy-prone rat, which will need confirmation in other audiogenic seizure models.

Acoustic Stimulation↗
PubMed1998

In vitro electrophysiology of neurons in subnuclei of rat inferior colliculus.

We compared membrane and synaptic properties of neurons in the three major subdivisions of inferior colliculus (IC), central nucleus (ICc, N=18), external cortex (ICx, N=38), and dorsal cortex (ICd, N=31) of slices from rat IC, using intracellular neuronal recording. Three types of responses occurred in each IC subdivision in response to depolarizing currents: on-type (N=20), rapidly-adapting (N=11), and sustained firing (N=56), which was most common. The on-type neurons have lower input resistances and shorter time constants, with wider and lower amplitude action potentials (APs) than sustained neurons. A calcium-mediated 'hump' was often evoked by depolarizing current pulses in ICd neurons (11 of 28), was infrequent in ICx, but was absent in ICc. ICx and ICc neurons often exhibited spontaneous repetitive spike firing, lower repetitive AP firing thresholds, and faster repetitive spike firing than ICd neurons. Calcium-mediated fast after-hyperpolarizations and spike frequency adaptation were regularly seen in IC. Neurons in ICx and ICd, but not ICc, had synaptic responses to stimulation of the collicular commissure (CoIC). In ICx, large epileptiform depolarizing events were often elicited by strong electrical stimulation of CoIC, which was not normally seen in ICd. These results indicate that ICx neurons exhibit a greater degree of synaptic excitability than neurons in ICc or ICd, which may contribute to the proposed role of ICx in pathological IC hyperexcitability.

Action Potentials↗
PubMed1997

Audiogenic kindling increases neuronal responses to acoustic stimuli in neurons of the medial geniculate body of the genetically epilepsy-prone rat.

Frequent repetition of audiogenic seizure (AGS) ('AGS kindling') in the severe substrain of genetically epilepsy-prone rats (GEPR-9s) results in the appearance of cortical epileptiform electrographic activity, increases of seizure duration and additional convulsive behaviors. These findings suggest that the initial AGS network, which is located primarily in the brainstem, has undergone expansion to the forebrain. The medial geniculate body (MGB) is a thalamic structure that is the first major auditory nucleus efferent to the AGS-initiating site in the inferior colliculus. The MGB is not required for AGS induction, but it has been implicated in the expanded AGS network in GEPR-9s based on focal, pharmacological blockade experiments. The present study examined changes in acoustically evoked MGB neuronal responses in awake and behaving GEPR-9s and in anesthetized GEPR-9s after 14 repetitive AGS-inducing stimuli given daily. An elevated number of action potentials was observed in the MGB neuronal responses after AGS kindling in GEPR-9s. This increase of MGB neuronal responses was associated with a loss of habituation and lasted for at least 28 days after the 14th AGS. An increase in the incidence of sustained acoustic responses in MGB neurons was observed after repetitive AGS in GEPR-9s. Increases in the peak latency and threshold of MGB neuronal responses were also observed after AGS kindling. MGB neurons exhibited a rapid tonic firing during tonic seizures in behaving GEPR-9s, suggesting that the MGB may be implicated in the propagation of seizure activity. However, MGB neuronal firing was silent during post-tonic clonus, a behavior seen in GEPR-9s only after AGS repetition, suggesting that MGB does not play a direct role in the generation of this convulsive behavior. Thus, changes in neuronal firing in nuclei efferent to the MGB, in the expanded neuronal network for repetitive AGS, may be responsible for the generation of post-tonic clonus in GEPR-9s.

Acoustic Stimulation↗
PubMed1997

Aberrant neuronal responsiveness in the genetically epilepsy-prone rat: acoustic responses and influences of the central nucleus upon the external nucleus of inferior colliculus.

The inferior colliculus (IC) central nucleus (ICc), is critical for audiogenic seizure (AGS) initiation in the genetically epilepsy-prone rat (GEPR). The ICc lacks direct motor outputs but sends a major projection to the external nucleus of IC (ICx), which does project to the sensorimotor integration nuclei within the AGS neuronal network. The present study compared acoustic responses of ICx neurons in the GEPR and normal anesthetized rat and evaluated whether the GEPR exhibits functional abnormalities in the pathway from ICc to ICx. There is a significantly greater incidence of sustained repetitive response patterns to the acoustic stimulus in GEPR ICx neurons (75%) than in normal ICx neurons (24%). Following unilateral microinjection of N-methyl-D-aspartate (NMDA) into the contralateral ICc, acoustically-evoked ICx excitation and inhibition were each increased in normal animals, which is consistent with the mixed projections previously reported in this pathway and observed with electrical stimulation in the present study. The NMDA-induced ICx firing increase may be relevant to AGS, since, in previous studies, bilateral focal microinjection of NMDA into the ICc induced AGS susceptibility in normal rats [23]. However, the incidence and degree of the ICx neuronal response changes after NMDA microinjection was not abnormal in the GEPR. These data suggest that the hyperresponsiveness of ICx neurons may not involve abnormal transmission between the ICc and ICx, despite the elevated ICx neuronal responses to acoustic stimuli. However, the ICx hyperresponsivess of the GEPR, which is likely due to the known decrease in effectiveness of GABA-mediated inhibition in GEPR neurons, may be a major mechanism subserving the critical role that this structure plays in the AGS network.

Acoustic Stimulation↗