Effects of substantia nigra γ-vinyl-GABA infusions on flurothyl seizures in adult rats

Xu, S.G.; Garant, Douglas S.; Sperber, Ellen F.; Moshé, Solomon L.

doi:10.1016/0006-8993(91)91687-v

Cited by 26 publications

(12 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: In Vivo Studiesmentioning

confidence: 90%

“…Only rats with bilateral symmetrical placements of both cannulae in the SNR were used. We have found previously that drug infusions above the SNR have no effect on flurothyl seizure threshold (Xu et al, 1991;Velíšková et al, 1998).For clarity of the comparisons in the graphic presentation of the data, we added in Figure 2, an inset showing the original, already published, data (Velíšková and Moshé, 2001) of the effects of SNR muscimol infusions on flurothyl seizure threshold at PN15 males, PN15 females, and PN15 neonatally castrated males. In vitro studies-For the in vitro gramicidin perforated patch clamp studies we used the following groups of rats: intact males and females, males castrated at PN0, females treated with TP, DHT or DES between PN0-PN2, and males castrated at PN3 (which were thus exposed to natural testosterone for three days).…”

mentioning

confidence: 99%

See 1 more Smart Citation

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Giorgi

Velı́šková

Chudomel

et al. 2007

Neurobiology of Disease

View full text Add to dashboard Cite

GABAergic activation of substantia nigra pars reticulata (SNR) at postnatal day (PN) 15 has sexspecific features on seizure control in vivo and electrophysiological responses in vitro. In males, the GABA A -receptor agonist muscimol has proconvulsant effects and induces depolarizing responses. In females, muscimol has no effect on seizures and evokes hyperpolarizing responses. We determined the time period during which sex hormones must be present to produce the sex-specific muscimol effects on seizures and their influence on SNR GABA A receptor-mediated postsynaptic currents. Exposure to testosterone or its metabolites (estrogen or dihydrotestosterone) during PN0-2 in females or males castrated at PN0 was sufficient to produce proconvulsant muscimol effects but did not affect the in vitro GABA responses, which remained hyperpolarizing. The data suggest that the PN0-2 period is critical for the development of the seizure-controlling SNR system; the hormonal effect on seizure control is independent from their effect on GABA conductance. Keywords substantia nigra; sex hormones; muscimol infusions; seizure; GABA; patch clamp During development, circulating sex hormones have organizational effects leading to permanent differences between males and females in distinct brain regions (Gorski, 1984). The presence or absence of testosterone, acting via its metabolites, dihydrotestosterone and estrogen, determines the future "male" or "female" brain phenotype (McEwen, 1992). In humans, the incidence of epilepsy is higher in the youngest age groups and population studies have shown that males have a higher incidence of seizures than females (Hauser, 1997). These epidemiological data strengthen the need to understand mechanisms underlying the sexdependent differentiation of the CNS, especially in relation to structures involved in seizure Correspondence: Jana Velíšková, MD, PhD, Albert Einstein College of Medicine, Department of Neurology, K312, 1410 Pelham Parkway South, Bronx, NY 10461, USA, Phone: (718) 430-2469, Fax: (718) The substantia nigra pars reticulata (SNR), a midbrain structure populated largely by GABAergic neurons, serves as a main output of the basal ganglia. The SNR is involved in the control of seizures in an age-and sex-specific fashion (Velíšková and Moshé, 2001;Velíšková and Moshé, 2006). In immature rats [postnatal day (PN) 15], localized bilateral SNR microinfusions of muscimol, an agonist at GABA A receptors, have proconvulsant effects on flurothyl-induced clonic seizures in males but not in females (Moshé et al., 1994;Velíšková and Moshé, 2001). Additionally, in vitro gramicidin patch clamp recordings in slices from PN14-17 males and females show sex-specific responses of the SNR GABAergic neurons to bath application of muscimol (Galanopoulou et al., 2003b) and to synaptically released GABA (Kyrozis et al., 2006). In males, both have depolarizing effects on the membrane potential of the SNR GABAergic neurons, while in females the response is hyperpolarizing.The majority of sex differenc...

show abstract

Section: In Vivo Studiesmentioning

confidence: 90%

mentioning

confidence: 99%

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Giorgi

Velı́šková

Chudomel

et al. 2007

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

“…Doses of the presynaptic GABA agonist y-vinyl-GABA (GVG) that increase GABA in SNR result in the suppression of fluorothyl seizures in both adult (10) and 16-day-old rats (1 1). Doses of the presynaptic GABA agonist y-vinyl-GABA (GVG) that increase GABA in SNR result in the suppression of fluorothyl seizures in both adult (10) and 16-day-old rats (1 1).…”

Section: Discussionmentioning

confidence: 99%

“…For seizure testing, all rats received simultaneous bilateral intracerebral microinjections of either muscimol or THIP (Sigma Chemical, St. Louis, MO, U.S.A.) or saline through injector cannulae acutely inserted in implanted guide cannulae, and the drug doses and pretest intervals for microinjections were chosen based on previous studies in SNR (8,10,13). Behavioral effects of the drugs were assessed during the 30-min interval before seizure testing.…”

Section: Methodsmentioning

confidence: 99%

Age‐Related Differences in the Effects of GABA, Agonists Microinjected Into Rat Substantia Nigra: Pro‐ and Anticonvulsant Actions

Garant

Sperber

et al. 1995

Epilepsia

Self Cite

View full text Add to dashboard Cite

GABAergic transmission in the substantia nigra pars reticulata (SNR) has an important role in the control of experimental seizures. In the flurothyl seizure model, SNR microinjection of the selective GABAA receptor agonist muscimol results in a biphasic dose-response curve in adults: Intermediate doses are anticonvulsant, but high doses have proconvulsant effects. Another GABAA agonist, THIP (4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol), also produces anticonvulsant effects at lower doses, whereas higher doses tend to produce a proconvulsant effect. In 16-day-old rat pups, no anticonvulsant but only proconvulsant effects of muscimol occur, and at lower doses than in adults. These data suggest that the immature SNR is significantly more sensitive to the proconvulsant effects of GABAA receptor agonists than is the SNR of adults. We hypothesize that the age-related differences in nigral GABAergic response may be due to ontogenic changes in GABAA-sensitive neuronal circuits in the SNR.

show abstract

“…This subcortical region has been implicated in the modulation and propagation of generalized seizures (Gale 1992;Gale et al 1993;Sawamura et al 2001). Specifically, there is evidence that the substantia nigra pars reticulata, a region rich in GABAergic neurons projecting to the superior colliculus and pedunculopontine tegmental nucleus plays a pivotal role in seizure propagation and is involved during the propagation of flurothyl induced seizures (Iadarola and Gale 1982;Gale 1985;Toussi et al 1987;Xu et al 1991;Veliskova et al 2002Veliskova et al , 2005.…”

Section: Altered Seizure Thresholdmentioning

confidence: 99%

GABAergic Interneuron Development and Function Is Modulated by the Tsc1 Gene

Fu¹,

Cawthon²,

Clinkscales³

et al. 2011

Cerebral Cortex

106

View full text Add to dashboard Cite

Tuberous sclerosis complex (TSC) is a genetic disease with severe neurologic and psychiatric manifestations including epilepsy, developmental delay, and autism. Despite much progress in defining abnormal signaling pathways including the contribution of increased mTORC1 signaling, specific abnormalities that underlie the severe neurologic features in TSC remain poorly understood. We hypothesized that epilepsy and autism in TSC result from abnormalities of γ-aminobutyric acidergic (GABAergic) interneurons. To test this hypothesis, we generated conditional knockout mice with selective deletion of the Tsc1 gene in GABAergic interneuron progenitor cells. These interneuron-specific Tsc1 conditional knockout (CKO) mice have impaired growth and decreased survival. Cortical and hippocampal GABAergic interneurons of CKO mice are enlarged and show increased mTORC1 signaling. Total numbers of GABAergic cells are reduced in the cortex with differential reduction of specific GABAergic subtypes. Ectopic clusters of cells with increased mTORC1 signaling are also seen suggesting impaired interneuron migration. The functional consequences of these cellular changes are evident in the decreased seizure threshold on exposure to the proconvulsant flurothyl. These findings support an important role for the Tsc1 gene during GABAergic interneuron development, function, and possibly migration.

show abstract

Effects of substantia nigra γ-vinyl-GABA infusions on flurothyl seizures in adult rats

Cited by 26 publications

References 31 publications

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

The role of substantia nigra pars reticulata in modulating clonic seizures is determined by testosterone levels during the immediate postnatal period

Age‐Related Differences in the Effects of GABA, Agonists Microinjected Into Rat Substantia Nigra: Pro‐ and Anticonvulsant Actions

GABAergic Interneuron Development and Function Is Modulated by the Tsc1 Gene

Contact Info

Product

Resources

About