Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABAB receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABAB receptors are usually only observed after coexpression of GABAB(1) and GABAB(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABAB(1) is responsible for binding of GABA, whereas GABAB(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABAB(1) subunit is also essential for all GABAB signaling in vivo. Mice lacking the GABAB(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABAB agonists. However, GABAB(1) exhibits a broader cellular expression pattern than GABAB(2), suggesting that GABAB(1) could be functional in the absence of GABAB(2). We now generated GABAB(2)-deficient mice to analyze whether GABAB(1) has the potential to signal without GABAB(2) in neurons. We show that GABAB(2)-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABAB(1)-/- mice. This clearly demonstrates that the lack of heteromeric GABAB(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABAB(1)-/- mice, we still detect atypical electrophysiological GABAB responses in hippocampal slices of GABAB(2)-/- mice. Furthermore, in the absence of GABAB(2), the GABAB(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABAB(2) with GABAB(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABAB receptors exist in neurons that naturally lack GABAB(2) subunits.
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PMID:Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. 1524 Aug

Memory impairment is a common consequence of epileptic seizures. The hippocampal formation is particularly prone to seizure-induced amnesia due to its prominent role in mnemonic processes. We used the isolated CA1 slice preparation to examine effects of seizure-like activity on hippocampal plasticity, long-term potentiation (LTP), and long-term depression (LTD). Repeated spontaneous ictal events, generated in the presence of antagonists of GABA(A) receptor function, led to a stepwise erasure of LTP (termed spontaneous depotentiation, SDP). SDP could be initiated at various stages of LTP consolidation (tested < or =120 min after the induction of LTP). Renewed tetanic stimulation re-established LTP. SDP was remarkably specific: baseline transmission and other forms of hippocampal plasticity, i.e., Ca(2+)-induced LTP and two forms of LTD [(RS)-3,5-dihydroxyphenyglycine (DHPG) mediated and low-frequency stimulation mediated] were not affected by the same type of seizure activity. SDP was blocked in the presence of the group I mGluR antagonist (S)-4-carboxyphenylglycine. The mGluR1 antagonist (S)-(+)-alpha-amino-methylbenzeneacetic acid blocked approximately 80%, the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)-pyridine approximately 30% of SDP. Most efficient implementation of SDP was observed during seizures in the combined presence of the group I mGluR agonist DHPG and the GABA(A) antagonist bicuculline. However, similar ictal activity generated in the presence of DHPG alone did not lead to SDP in the vast majority of recordings. Complete disinhibition and at least partial activation of group I mGluR were necessary conditions for the induction of SDP. The depotentiating pharmacological conditions were accompanied by tonic membrane depolarization of CA1 pyramidal cells. Since hyperpolarization (by negative current injection) prevented intracellular SDP under depotentiating pharmacological conditions and depolarization (by positive current injection) led to selective intracellular SDP in the non-depotentiating seizure protocol of DHPG, it is concluded that cell depolarization was a sufficient condition for seizure-like activity to reverse hippocampal LTP.
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PMID:Reversal of hippocampal LTP by spontaneous seizure-like activity: role of group I mGluR and cell depolarization. 1528 58

Juhn Wada developed a test while in Montreal designed to definitively confirm hemispheric lateralization of speech in candidates for surgical treatment of epilepsy. By unilateral intra-carotid administration of a bolus of a general anesthetic, classically sodium amobarbital, function can be tested in the non-injected hemisphere, while the injected side is dysfunctional. The test has been expanded to test memory functions in the hemisphere (temporal lobe) contralateral to expected surgery (memory reserve) in the hope of contra-indicating surgery that may result in global amnestic syndromes (patient HM). Conversely, risk of material-specific memory loss following surgery can be assessed by testing memory in the hemisphere/temporal lobe to be operated ("functional adequacy"). Memory dysfunction, when concordant with EEG seizure onset and chosen side of temporal lobe surgery has also been shown to correlate with favourable post-operative seizure outcome. Nevertheless, the test remains invasive, requiring an angiogramme. Non-invasive alternatives such as fMRI and PET and their reported reliability compared to a Wada test are discussed. A world-wide shortage of amobarbital has led to the use of some other anesthetic agents. Overall, the indications for the test and the manner in which it is performed vary greatly from one institution to the next. It is used almost systematically in some institutions and very rarely in others. Future perspectives are discussed.
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PMID:[What is the current role of a Wada test in the pre-surgical work-up of pharmacologically intractable epilepsy in adults?]. 1533 62

Background. We have previously described the resection of hypothalamic hamartomas (HH) using a transcallosal approach [Transcallosal resection of hypothalamic hamartomas, with control of seizures, in children with gelastic epilepsy, Neurosurgery, 2001]. Since then, we have refined the technique and now describe in detail an anterior transcallosal transseptal interforniceal approach to the third ventricle as a variation of the standard transcallosal interforniceal approach. The results of this series are presented to demonstrate the safety and efficacy of this approach. Method. HH were resected via an anterior transcallosal, transseptal, interforniceal approach to the third ventricle. This is a more anterior approach to the third ventricle with a more acute trajectory than has been described previously. Results. This approach provided excellent access to the floor of the third ventricle with minimal forniceal retraction and avoidance of dissection of the deep venous structures. Transcallosal resection of HH was performed in 45 patients aged 2.9-33 years (mean 11.3 years). Morbidity was minimal, including transient hemiparesis in 3, ongoing diabetes insipidus in 2, early short-term memory impairment in 16 (persistent in 6) and one patient developed pneumonia postoperatively but recovered. Conclusion. The anterior transcallosal transseptal interforniceal technique is an effective and relatively safe technique when used for the resection of HH. This operative approach is applicable to other pathology in the third ventricle or hypothalamic region and has advantages compared with the standard transcallosal approach to the third ventricle.
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PMID:Operative technique: the anterior transcallosal transseptal interforniceal approach to the third ventricle and resection of hypothalamic hamartomas. 1533 37

Soman, an anticholinesterase and dangerous nerve agent, produces convulsions, memory impairment, and cell loss in the brain, especially in the hippocampus. Soman-induced accumulation of acetylcholine initiates mechanisms responsible for the development of incapacitating seizures. The prolonged epileptiform nature of these seizures causes the release of another excitatory neurotransmitter, glutamate, which has been linked to the toxic action of the nerve agent. Here, we tested whether subtoxic soman exposures influence the brain's sensitivity to glutamate-based excitotoxicity. Over a 1-week period, hippocampal slice cultures were exposed daily to a transient level of soman that produced no evidence of synaptic deterioration. After the subtoxic soman treatments, however, the tissue became vulnerable to a brief episode of glutamate receptor overstimulation that normally resulted in little or no excitotoxic damage. In those slice cultures treated with subtoxic soman, a decline in synaptic markers as well as an increase in spectrin breakdown occurred 24 hr after the mild excitotoxic event. Exposure to high soman concentrations alone produced similar synaptic degeneration, but without evident cell death, suggesting that synaptic decline is an early neurotoxicological response to the nerve agent. Interestingly, enhanced excitotoxic sensitivity caused the brain tissue to become susceptible to disparate insults initiated before or after the soman contact. These findings indicate that seemingly innocuous soman exposures leave the hippocampus sensitive to the types of insults implicated in traumatic brain injury and stroke. They also warn that asymptomatic contact with soman may lead to progressive synaptopathogenesis and that early indicators of soman exposure are critical to prevent potential brain injury.
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PMID:Repeated contact with subtoxic soman leads to synaptic vulnerability in hippocampus. 1535 21

Cognitive profiles in epilepsy are as heterogenous as the epileptic syndromes themselves; causes, topography of epileptogenic areas, pathogenetic mechanisms, and the diverse features characterising the clinical course all contribute to the effect on cognition. Chronic epilepsy generally impairs cognition, but it also induces processes of functional reorganisation and behavioural compensation. In most idiopathic epilepsies, cognition is only mildly deteriorated or even normal by clinical standards. Localisation-related cryptogenic and symptomatic epilepsy disorders are accompanied by focal deficits that mirror the specific functions of the respective areas. Poor cognitive outcome is generally associated with an early onset and a long duration of the disease and with poor seizure control. There is evidence that cognitive functions are already impaired at the onset of the disease, and that the maturation of cognitive functions in children is susceptible to the adverse influence of epilepsy. In adults, cognitive decline progresses very slowly over decades with an age regression similar to that of people without epilepsy. Successful epilepsy surgery can stop or partly reverse the unfavourable cognitive development, but left-temporal resections in particular have a high risk of additional postoperative verbal memory impairment. Cognitive recovery in the adult brain after successful surgery indicates functional compensation and, to some degree, functional reorganisation or a reactivation of functions previously suppressed by influence from distant but connected epileptogenic areas.
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PMID:Chronic epilepsy and cognition. 1548 59

Our objective was to investigate if MRI-determined hippocampal atrophy (HA) is associated with memory deficits independent of seizure frequency. We studied three groups of individuals: (1) 10 asymptomatic first-degree relatives of patients with familial mesial temporal lobe epilepsy (FMTLE), all of them with HA; (2) 14 patients with benign FMTLE, 9 with HA, and 5 with normal hippocampal volumes; and (3) 16 patients with refractory FMTLE, all but one with HA. HA was associated with lower scores on general memory (P=0.015), verbal memory (P=0.020), and delayed recall (P=0.028), even in those with no or few seizures in life. General linear model analyses showed that the interaction between seizure outcome and HA was associated with worse verbal memory (P=0.029), visual memory (P=0.022), and delayed recall (P=0.039) as compared with each of these factors independently. Our findings suggest that seizures and HA are independently associated with memory impairment.
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PMID:Evidence of memory impairment in asymptomatic individuals with hippocampal atrophy. 1558 48

Limbic encephalitis affects the mesial temporal lobes and is characterized by subacute onset of memory impairment, personal change, temporal seizures and autonomic nervous disorders. It can occur as viral infections, especially caused by Herpes simplex, paraneoplastic syndrome as a remote effect of cancer, CNS complication of well defined autoimmune diseases. Recently acute reversible limbic encephalitis which probably autoimmune mediated disorders has been reported. Anti-immunotherapy including steroids, plasma exchange and intravenous immunoglobulin often improves this condition and anti-voltage gated potassium channel (VGKC) antibody or anti-glutamate receptor epsilon2 antibody has been detected in some patients. Establishing the means of early detection of these antibodies as well as other characteristic paraneoplastic antibodies should now be the aim. Detection of neurotropic viral genomes in CSF by PCR is also important for differential diagnosis. As complete recovery of higher cerebral function is generally difficult, immunotherapy and anti-convulsants in addition to vitamin B, and acyclovir should be considered in an early stage of disease.
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PMID:[Limbic encephalitis: etiology, pathogenesis, diagnosis and therapy]. 1565 Dec 95

Paraneoplastic limbic encephalitis (PLE) is a rare neurological consequence of a variety of cancers, most commonly originating from lung, breast and testis. The aetiology is believed to be immune-mediated, caused by tumour-induced autoimmunity launching an attack against one's own central nervous system. The patient may present with amnesia, depression, anxiety, seizures and/or personality changes. The onset of these symptoms may precede the diagnosis of malignancy by a period of up to 2 years. The malignancy may be occult and unless the syndrome is recognised, it may fail to be detected. The diagnosis of PLE is suggested by the clinical picture, MRI evidence of mesial temporal lobe abnormality and CSF abnormalities such as the presence of oligoclonal bands. It may be further supported by the presence of paraneoplastic antibodies in the serum. Immunosuppression has been tried in some cases but memory impairment is often irreversible. There are several case reports in the literature of paraneoplastic limbic encephalitis but few emphasise the resulting impact that this may have on the patient's quality of life and their carers. The accompanying amnesia is often far more distressing to the carers, who are aware of the limitations of treatment of the underlying malignancy. Hospices offer the appropriate palliative environment for such patients as well as physical and psychological respite to the carers.
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PMID:Paraneoplastic limbic encephalitis. 1570 28

Adult rats with early-life frequently repetitive febrile seizures (FRFS), but not single febrile seizure (SFS), exhibited impaired performance in inhibitory avoidance tasks but without significant hippocampal neuronal loss. The mechanisms of long-term memory impairment in the hippocampus of adult rats with early-life FRFS remain unknown. Using a heated-air febrile seizures (FS) paradigm, male rat pups were subjected to single or nine episodes of brief FS at days 10 to 12 postpartum. We found that early-life FRFS led to long-term bidirectional modulation in hippocampal synaptic plasticity, i.e., impaired long-term potentiation and facilitated long-term depression. Three hours after inhibitory avoidance training, phosphorylation of hippocampal extracellular signal-regulated kinase (ERK) 1/2 was significantly less in the FRFS group than in controls. Furthermore, there was a selective alteration in NMDA receptor-mediated ERK1/2 phosphorylation in the hippocampus of the FRFS group. Although the expression levels of NMDA receptor subunits and interaction of NMDA receptor and postsynaptic density 95 did not alter quantitatively, there was a specific alteration in NR2A, but not NR2B, subunit tyrosine phosphorylation after NMDA stimulation in the FRFS group. These data offer a potential molecular explanation for the hippocampus-dependent memory deficits observed in the rats with early-life FRFS.
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PMID:Repetitive febrile seizures in rat pups cause long-lasting deficits in synaptic plasticity and NR2A tyrosine phosphorylation. 1575 73


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