PubMed HealthSearch

PubMed · 2839355

Decrease in excitatory transmission within the lateral habenula and the mediodorsal thalamus protects against limbic seizures in rats.

Abstract

We have used limbic convulsions induced by systemic pilocarpine in rats combined with focal intracerebral injections concurrently to study the initiation and spread of seizure activity. Protection against pilocarpine-seizure development by antagonism of excitatory or facilitation of inhibitory neurotransmission at focal sites establishes the anatomical circuits involved in the propagation of seizures. The excitatory amino acid antagonist 2-amino-7-phosphonoheptanoate (APH, selective for the NMDA preferring glutamate receptor subtype) is potently anticonvulsant after bilateral focal injections into the habenula or mediodorsal thalamus. The dose of APH required to give sustained protection against pilocarpine-induced convulsions is 10 pmol for lateral habenula and 50 pmol for mediodorsal thalamus. The GABA agonist muscimol produces a similar sustained protection following focal injections (100 pmol/side) into either the lateral habenula or the mediodorsal thalamus. An overall decrease in the efferent neurotransmission of these two brain regions results in a strong anticonvulsant effect indicating their importance in modulating limbic seizure activity.

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

S Patel, M H Millan, B S Meldrum. 1988. Decrease in excitatory transmission within the lateral habenula and the mediodorsal thalamus protects against limbic seizures in rats.. https://doi.org/10.1016/0014-4886(88)90065-9

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

Nucleus-specific chloride homeostasis in rat thalamus.

Synchronous thalamic network activity occurring during slow wave sleep and paroxysmal discharges critically depends on the ability of thalamocortical relay cells and inhibitory neurons of the nucleus reticularis thalami (nRt) to fire bursts of action potentials. Inhibitory synaptic potentials (IPSPs) originating from nRt cells are crucial in deinactivating T-channels and thus promoting burst firing in relay cells, but the functional role of intra-nRt IPSPs is less well understood. A major factor that regulates the net effects of IPSP generation is the chloride equilibrium potential (ECl). Here we applied the perforated patch-clamp technique, using the cation-selective ionophore gramicidin to assess the reversal potential of chloride in nRt and relay cells in brain slices. We found that the reversal potential of GABA-induced membrane currents (EGABA) was significantly more hyperpolarized in relay (-81 +/- 2.6 mV), as compared with nRt cells (-71 +/- 2.5 mV). EGABA was not significantly different from the reversal potential of evoked IPSCs (EIPSC; -82 +/- 4.4 mV) in relay cells. In both relay and reticular neurons the chloride gradient was collapsed partially by the chloride cation cotransport blocker furosemide, suggesting an active chloride extrusion mechanism in thalamic neurons. Given the relatively hyperpolarized resting potentials (approximately -70 mV) reported for nRt and relay cells during in vitro thalamic oscillations, we conclude that under these conditions GABAA IPSPs lead to significant hyperpolarization in relay cells. By contrast, intra-nRt inhibition essentially would be shunting, i.e., would produce minimal membrane polarization but still could reduce the amplitude of excitatory events.

2-Amino-5-phosphonovalerate

Nitric oxide facilitates long-term potentiation, but not long-term depression.

Reports that nitric oxide synthase (NOS) inhibition prevents the induction of long-term potentiation (LTP) have been controversial. Recent evidence suggests that NO may help to regulate the threshold for LTP induction. We have tested this hypothesis by examining the effects of stimulus frequency and train duration on synaptic plasticity in the presence of either NO donors or NOS inhibitors. Two different NO donors facilitated LTP induction by stimuli that normally produced only short-term potentiation, whereas NOS inhibitors blocked LTP to stimuli that normally produce small LTP. NO donors facilitated LTP induction even when NMDA receptors were blocked, indicating that NO need not act via NMDA receptors. NO donors and NOS inhibitors were without effect on long-term depression (LTD), suggesting that they act on a distinct potentiating mechanism. Thus, NO could contribute to the establishment of plasticity under physiologically relevant conditions by selectively increasing the probability of LTP induction.

2-Amino-5-phosphonovalerate

N-methyl-D-aspartate-mediated glutamate toxicity in the developing rabbit retina.

Extracellular levels of endogenous glutamate are relatively high in the developing rabbit retina but nonetheless appear to promote cell survival and developmental processes at concentrations considered toxic in the adult. We wished to examine the development of retinal susceptibility to glutamate toxicity as well as the protective effects of two N-methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphono-5-valeric acid (APV) and dextromethorphan (Dex), and the nitric oxide synthase (NOS) inhibitor, NG-methyl-L-arginine (metARG). One day in vitro retinal explants of adult and neonatal rabbits were incubated with various agonists and antagonists, and stained with trypan blue to visualize necrotic cells. The density of the necrotic cells was analyzed using the Zeiss Videoplan 2. Immature neurons were approximately 10-fold less sensitive to NMDA toxicity compared to the adult. Although both NMDA antagonists and metARG provided marked protection for adult retinal neurons against glutamate toxicity, the modest susceptibility of the immature neuron was blocked only by Dex and not APV or metARG. At least two factors may contribute to the ability of the neonatal retina to survive in the presence of high levels of endogenous extracellular glutamate. First, the 10-fold developmental increase in NMDA toxicity occurs simultaneously with a 12-15-fold downregulation of extracellular glutamate, probably through the actions of maturing Muller cells. Second, the NMDA/NO excitotoxic pathway may not be active at birth since an NOS inhibitor had little effect at this stage and our previous morphological data demonstrate that NOS-containing cells are not present in their mature configuration until the second postnatal week.

2-Amino-5-phosphonovalerate