Download Carl L.Faingold, Manish Raisinghani, Prosper N`Gouemo

Chapter 26
Neuronal Networks in Epilepsy
Comparative Audiogenic Seizure
Networks
Carl L.Faingold, Manish
Raisinghani, Prosper N'Gouemo
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 26.1 Comparative network diagrams in three forms of audiogenic seizures: GEPR-9s (left panel), GEPR-3s
(middle panel), and ETX rats (right panel). The required network structures in all three models begins in the auditory
network [the cochlear nucleus (CN) and superior olivary complex (SOC)], which project to the critical hub in the inferior
colliculus (IC). The IC projects to the deep layers of the superior colliculus (DLSC) and brainstem conditional
multireceptive regions, including the (pontine) brainstem reticular formation (BRF) and ventrolateral periaqueductal gray
(PAG) and substantia nigra reticulata (SNr). These structures project to the spinal cord, which generates the wildrunning and tonic seizures, which end in tonic extension of the hind limbs in GEPR-9s and which end in forelimb clonus
in GEPR-3s and ETX rats (with some variability). However, in the GEPR-3s and ETX rats, the amygdala (AMG) is also
involved in the network, and the medial geniculate body (MGB) is implicated, since this structure is the likely pathway
from the IC to the AMG. The hippocampus (HPC) is implicated in the network for ETX. The cortex is not involved in
either GEPR-9s or GEPR-3s unless further intervention occurs (see Chapter 27).
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FIGURE 26.2 Composite behavioral activity in GEPR-9s and concurrent typical examples of neuronal firing in the major
network nuclei for AGS seen during each seizure behavior. The structures include the (A) inferior colliculus central (ICc)
nucleus; (B) inferior colliculus external (ICx) nucleus; (C) deep layers of the superior colliculus (DLSC); (D)
periaqueductal gray (PAG); (E) pontine brainstem reticular formation (PRF); and (F) substantia nigra reticulata (SNr).
Thus, ICc and ICx firing is greatest during AGS initiation, while the greatest increase in DLSC neuronal firing occurs at
the onset of wild running. The greatest increases in PAG, SNr, and PRF neuronal firing occur during the tonus and tonic
hindlimb extension phases of AGS. The PRF and SNr are the only areas active during postictal depression of
consciousness. Note: Recovery of SNr firing occurred but was not recorded in the example in (F). Acoustic stimulus
parameters: 12 kHz tone burst, 100 ms duration, 5 ms rise-fall, 100 dB SPL, 2–4 Hz repetition rate. Each row is from
the same rat.
(Source: Drawings courtesy of Naritoku et al. From Faingold by permission.)
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 26.3 GABA-mediated inhibition defects in GEPR-9s: GABAergic neurotransmission normally plays a critical role in determining the
responses of the inferior colliculus (IC) to acoustic stimulation, and defects in specific forms of inhibition are key causative factors in audiogenic
seizure initiation. Line (A) illustrates binaural inhibition common in ICc neurons. In the poststimulus time histogram (PSTH) example in line (A)
(“Normal” column), binaural presentation of the stimulus results in a greatly reduced number of action potentials (N), as compared to the response
to the same stimulus to one ear (monaurally to the contralateral ear). In GEPR-9 ICc neurons, the effect of binaural inhibition is significantly
reduced, as shown in this example by the comparison of the line (A) (“GEPR-9” column) example when the sound is presented to both ears
(binaural). This difference in effectiveness of GABA-mediated inhibition was significant, as shown by the bar graphs in line (A), illustrating the mean
normal versus GEPR IC data. This form of inhibition can be blocked by direct application of a GABAA antagonist onto ICc neurons.151 Line (B)
illustrates examples of high-intensity-induced inhibition (a nonmonotonic rate intensity response), which is a form of inhibition seen in many normal
ICc neurons when the intensity of the acoustic stimulus is increased, as shown by the rate–intensity curve in line (B) (“Normal” column), and this
inhibition can be blocked by application of a GABAA antagonist, bicuculline (BIC), directly onto these neurons, as also shown by the example in 3B
(“Normal” column). An example of the failure of this form of inhibition in the GEPR is shown in line (B) (“GEPR-9” column), and the significant mean
difference in the normal versus GEPR comparison is shown by the bar graph in line (B). A form of inhibition that occurs at the end of a finite
acoustic stimulus is called the offset response and is seen in a small percentage of normal ICc neurons, but it is often hard to detect [line (C),
“Control” column]. However, when BIC is applied directly onto many ICc neurons, this can cause an offset peak to appear by blocking offset
inhibition [line (C), “Normal” column, right panel]. In GEPR-9s, the incidence of failure of offset inhibition allowing the appearance of the offset
response are often induced by increasing the sound intensity [line (C), “GEPR-9” column, right panel]. The incidence of neurons showing the offset
peak was significantly greater in GEPR-9s as compared to normal rats, as shown by the bar graphs in line (C). Direct iontophoretic application of
GABA onto ICc neurons produces significant inhibition in acoustically evoked firing [line (D), “Normal” panel, right versus left panel at 2 nA of
GABA]. In GEPR-9s, the effectiveness of iontophoretically applied GABA was significantly reduced [line (D), “GEPR-9” column, right versus left
panel, 20 nA of GABA], despite the fact that this was applied using the same electrode in both rats. The mean difference in GABA effectiveness was
significant, as shown by the bar graphs in line (D). PSTH parameters = 25 or 50 stimulus presentations at 2/s of 100 ms 12 kHz tone bursts (100 ms
duration denoted by the heavy line beneath each PSTH; 5 ms rise-fall). N = number of action potentials per PSTH. ∗ Significantly different at p <
0.05; # significantly different at p < 0.02.
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FIGURE 26.4 In animals susceptible to AGS (in GEPRs and during ETX), paired-pulse inhibition in inferior colliculus
dorsal nucleus (ICd) neurons (in vitro) is replaced by facilitation as compared to responses in normal ICd neurons.
Paired-pulse inhibition was seen in normal (Norm) ICd neurons [(D) low intensity; (E) moderate intensity; (F) high
intensity] in response to increasing stimulus intensity in the IC commissure. In GEPRs, paired-pulse facilitation was
observed [(A) low intensity; (B) moderate intensity; (C) high intensity]. A similar effect was seen in ICd neurons during
ETX, as shown by the significant differences in the mean incidence of facilitation shown in the bar graphs in the right
panel. (Source: Based on Refs 152,153.) ∗ p < 0.05: Significantly different from normal controls (Student's t-test).
(Source: Reprinted from Faingold,30 with permission.)
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FIGURE 26.5 Compilation of mean acoustically evoked neuronal firing in GEPR-9s as a percentage, with normal
Sprague–Dawley rats as control (100%). The acoustic stimuli (12 kHz 100 ms tone burst) was at 90 dB (SPL Re 0.0002
dyn/cm2). Five AGS network sites are compared: the inferior colliculus (IC), deep layers of the superior colliculus
(DLSC), periaqueductal gray (PAG), pontine reticular formation (PRF), and substantia nigra reticulata (SNr). The mean
neuronal firing percentages were increased in all the network structures with the greatest increase in the consensus
AGS initiation site in the IC. Significantly different from control at ∗ p < 0.05 (Student's t-test).
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 26.6 Compilation of mean acoustic response threshold differences between GEPR-9s and normal Sprague–
Dawley rats. Five AGS network sites are compared: the inferior colliculus (IC), deep layers of the superior colliculus
(DLSC), periaqueductal gray (PAG), pontine reticular formation (PRF), and substantia nigra reticulata (SNr). In the IC,
DLSC, and PAG, the response thresholds are significantly above those of normal rats, consistent with the known
hearing deficit in these rats. However, in the PRF and SNr, the neuronal response threshold is significantly below that of
the neurons in the same structures in normal rats. Significantly different from control at ∗ p < 0.05 and ∗∗ p < 0.01
(Student's t-test).
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