Fetal raphe transplants reduce seizure severity in serotonin-depleted GEPRs

Clough, Richard W.; Statnick, Michael A.; Maring-Smith, M.L.; Wang, Congdong; Eells, Jeffrey B.; Browning, Ronald A.; Dailey, John W.; Jobe, P C

doi:10.1097/00001756-199612200-00067

Cited by 28 publications

(12 citation statements)

References 5 publications

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“…Neurosurgical destruction of serotoninergic terminals in the epileptic focus (olfactory bulb or amygdala) facilitated the initial development of kindling obtained by stimulations of these structures (Lerner‐Natoli, 1987). Transplantation of fetal raphe tissue promotes lasting reductions in increased seizure severity resulting from depletion of serotonin in the brain of genetically epilepsy‐prone rats (GEPR‐3s) (Clough et al, 1996). It suggests that median raphe 5‐HT system may involve in the desynchronization of the hippocampal EEG.…”

Section: Discussionmentioning

confidence: 99%

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Dong

Tang

Chen

et al. 2005

J of Neuroscience Research

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We showed that when CA3 pyramidal neurons in the caudal 80% of the dorsal hippocampus had almost disappeared completely, the efferent pathway of CA3 was rarely detectable. We used the mouse pilocarpine model of temporal lobe epilepsy (TLE), and injected iontophoretically the anterograde tracer phaseolus vulgaris leucoagglutinin (PHA-L) into gliotic CA3, medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei, or the retrograde tracer cholera toxin B subunit (CTB) into gliotic CA3 area of hippocampus. In the afferent pathway, the number of neurons projecting to CA3 from medial septum and the nucleus of diagonal band of Broca, median raphe, and lateral supramammillary nuclei increased significantly. In the hippocampus, where CA3 pyramidal neurons were partially lost, calbindin, calretinin, parvalbumin immunopositive back-projection neurons from CA1-CA3 area were observed. Sprouting of Schaffer collaterals with increased number of large boutons in both sides of CA1 area, particularly in the stratum pyramidale, was found. When CA3 pyramidal neurons in caudal 80% of the dorsal hippocampus have almost disappeared completely, surviving CA3 neurons in the rostral 20% of the dorsal hippocampus may play an important role in transmitting hyperactivity of granule cells to surviving CA1 neurons or to dorsal part of the lateral septum. We concluded that reorganization of CA3 area with its downstream or upstream nuclei may be involved in the occurrence of epilepsy.

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Section: Discussionmentioning

confidence: 99%

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Dong

Tang

Chen

et al. 2005

J of Neuroscience Research

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“…Considering that the human terminal autoreceptor is h 5‐HT 1B , the emerging pharmacological differences between h 5‐HT 1B and h 5‐HT 1D receptors may lead to the development of novel therapeutic agents. 5‐HT inhibition of glutamatergic transmission may be involved in a variety of pathological conditions, including epilepsy (Favale et al , 1995; see Clough et al , 1996 and references therein). Selective agonists at h 5‐HT 1D receptors, able to reduce abnormally elevated glutamate release without inhibiting 5‐HT release, may be effective anticonvulsants.…”

Section: Discussionmentioning

confidence: 99%

Glutamate release in human cerebral cortex and its modulation by 5‐hydroxtryptamine acting at h 5‐HT_1D receptors

Maura

Marcoli

Tortarolo

et al. 1998

British J Pharmacology

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1 The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2 The Ca 2+ -dependent K + (15 mM)-evoked over¯ow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC 50 =2.9 nM; maximal eect^50%). The inhibition caused by 5-HT was antagonized by the 5-HT 1 /5-HT 2 receptor antagonist methiothepin. The 5-HT 1B /5-HT 1D receptor agonist sumatriptan mimicked 5-HT (EC 50 =6.4 nM; maximal eect^50%); the eect of sumatriptan was also methiothepin-sensitive. Selective 5-HT 1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3 The 5-HT 1B /5-HT 1D receptor ligand GR 127935 and the 5-HT 2C /5-HT 1B /5-HT 1D receptor ligand metergoline were unable to prevent the 5-HT eect; instead they inhibited glutamate release, their eects being abolished by methiothepin. Some 5-HT 1A receptor antagonists also displayed intrinsic agonist activity. 4 The eect of sumatriptan was prevented by ketanserin, a drug known to display much higher anity for recombinant h 5-HT 1D than for h 5-HT 1B receptors. 5 We propose that neocortical glutamatergic nerve terminals in human brain cortex possess releaseinhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT 1D subtype.

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“…Further to test the hypothesis that the expression of forebrain seizure behavior is inversely related to the severity of brainstem seizures, we increased the severity of brainstem seizures in GEPR‐3s in an attempt to decrease the incidence of forebrain‐kindled behavior. From previous studies in our laboratory, it was known that widespread depletion of 5‐HT by intracerebral administration of 5,7‐DHT increased sound‐induced brainstem seizure severity in GEPR‐3s (13,30). As predicted, GEPR‐3s treated with 5,7‐DHT displayed less severe forebrain seizures, including a lower incidence of F&F clonus, during audiogenic kindling.…”

Section: Discussionmentioning

confidence: 99%

Brainstem Seizure Severity Regulates Forebrain Seizure Expression in the Audiogenic Kindling Model

Merrill¹,

Clough

Jobe

et al. 2005

Epilepsia

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Summary:Purpose: Although sound-induced (audiogenic) seizures in the genetically epilepsy-prone rat (GEPR) initially occur independent of the forebrain, repeated audiogenic seizures recruit forebrain seizure circuits in a process referred to as audiogenic kindling. In GEPR-3s, audiogenic kindling results in facial and forelimb (F&F) clonic seizures that are typical of forebrain seizures. However, in GEPR-9s, audiogenic kindling produces posttonic all-limb clonus not usually observed during forebrain seizures. We hypothesized that the more severe brainstem seizures of the GEPR-9 prevent the expression of F&F clonic seizures during audiogenic kindling. Therefore attenuation of audiogenic seizures during audiogenic kindling in GEPR9s should allow F&F clonic seizures to be expressed. Likewise, intensifying audiogenic seizure severity in GEPR-3s should inhibit audiogenically kindled F&F clonic seizures. We have tested this hypothesis in the present study.Methods: Lesions of the superior colliculus or treatment with low-dose phenytoin were used to suppress audiogenic seizure severity in GEPR-9s. Depletion of brain serotonin was used to increase the seizure severity in GEPR-3s. All GEPRs were then subjected to audiogenic kindling. Behavioral and electrographic seizures were assessed.Results: Suppression of audiogenic seizure severity during audiogenic kindling in GEPR-9s increased the incidence forebrain seizure behavior. Kindled GEPR-9s that continued to display full tonic seizures did not exhibit forebrain convulsions, but did show posttonic clonus and forebrain seizure activity in the EEG. GEPR-3s chronically depleted of brain serotonin, along with displaying tonic brainstem seizures, tended to display less severe forebrain seizures during audiogenic kindling.Conclusions: These findings support the concept that severe brainstem seizures prevent the behavioral expression of forebrain seizures in audiogenically kindled GEPR-9s. It appears that the severe brainstem seizure of the GEPR-9 does not allow the forebrain seizure to manifest its typical behavioral concomitants despite electrographic evidence that spike-wave discharge is occurring in the forebrain. Key Words: Brainstem seizureForebrain seizure-Kindling-Phenytoin.The sound-induced seizures of the genetically epilepsyprone rat (GEPR) are initiated and driven by a brainstem network independent of the forebrain (1). Two strains of GEPRs differ in seizure severity in response to intense auditory stimulation. GEPR-3s exhibit seizures characterized by an explosive running episode followed by loss of posture, paraxial extension, and generalized clonus of all limbs. GEPR-9s exhibit a more severe seizure characterized by an explosive run, followed by paraxial flexion and complete tonic extension of all limbs (see ref. 2 for a more complete description of the convulsive behavior). Earlier studies have shown that repetitive (daily) audiogenicinduced seizures result in the addition of seizure behavior that phenotypically mimics forebrain-seizure behavior (3-6). This activa...

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Fetal raphe transplants reduce seizure severity in serotonin-depleted GEPRs

Cited by 28 publications

References 5 publications

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Glutamate release in human cerebral cortex and its modulation by 5‐hydroxtryptamine acting at h 5‐HT_1D receptors

Brainstem Seizure Severity Regulates Forebrain Seizure Expression in the Audiogenic Kindling Model

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Fetal raphe transplants reduce seizure severity in serotonin-depleted GEPRs

Cited by 28 publications

References 5 publications

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Reorganization of CA3 area of the mouse hippocampus after pilocarpine induced temporal lobe epilepsy with special reference to the CA3‐septum pathway

Glutamate release in human cerebral cortex and its modulation by 5‐hydroxtryptamine acting at h 5‐HT1D receptors

Brainstem Seizure Severity Regulates Forebrain Seizure Expression in the Audiogenic Kindling Model

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Glutamate release in human cerebral cortex and its modulation by 5‐hydroxtryptamine acting at h 5‐HT_1D receptors