Glial glutamine synthetase is downregulated in the hippocampal sclerosis (HS) hippocampus of temporal lobe epilepsy (TLE) patients in areas with severe neuron loss. This downregulation appears to be pathology-related, rather than seizure-related, and may be part of the mechanism underlying impaired glutamate clearance found in the hippocampus of TLE patients with HS.

Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors involved in the regulation of glutamatergic transmission. Recent studies indicate that excitatory group I mGluRs (mGluR1 and mGluR5) contribute to neurotoxicity and hyperexcitability during epileptogenesis. In this study, we examined the distribution of mGluR1alpha and mGluR5 immunoreactivity (IR) in hippocampal resection tissue from pharmaco-resistant temporal lobe epilepsy (TLE) patients. IR was detected with panels of receptor subtype specific antisera in hippocampi from TLE patients without (non-HS group) and with hippocampal sclerosis (HS group) and was compared with that of non-epileptic autopsy controls (control group). By immunohistochemistry and immunoblot analysis, we found a marked increase of mGluR5 IR in hippocampi from the non-HS compared with the control group. High mGluR5 IR was most prominent in the cell bodies and apical dendrites of hippocampal principal neurons and in the dentate gyrus molecular layer. In the HS group, this increase in neuronal mGluR5 IR was even more pronounced, but owing to neuronal loss the number of mGluR5-immunoreactive neurons was reduced compared with the non-HS group. IR for mGluR1alpha was found in the cell bodies of principal neurons in all hippocampal subfields and in stratum oriens and hilar interneurons. No difference in mGluR1alpha IR was observed between neurons in both TLE groups and the control group. However, owing to neuronal loss, the number of mGluR1alpha-positive neurons was markedly reduced in the HS group. The up-regulation of mGluR5 in surviving neurons is probably a consequence rather than a cause of the epileptic seizures and may contribute to the hyperexcitability of the hippocampus in pharmaco-resistant TLE patients. Thus, our data point to a prominent role of mGluR5 in human TLE and indicate mGluR5 signalling as potential target for new anti-epileptic drugs.

Febrile seizures (FS) are the most prevalent seizures in children. Although FS are largely benign, complex FS increase the risk to develop temporal lobe epilepsy (TLE). Studies in rat models for FS have provided information about functional changes in the hippocampus after complex FS. However, our knowledge about the genes and pathways involved in the causes and consequences of FS is still limited. To enable molecular, genetic and knockout studies, we developed and characterized an FS model in mice and used it as a phenotypic screen to analyze FS susceptibility. Hyperthermia was induced by warm air in 10-to 14-day-old mice and induced FS in all animals. Under the conditions used, seizure-induced behavior in mice and rats was similar. In adulthood, treated mice showed increased hippocampal Ih current and seizure susceptibility, characteristics also seen after FS in rats. Of the seven genetically diverse mouse strains screened for FS susceptibility, C57BL/6J mice were among the most susceptible, whereas A/J mice were among the most resistant. Strains genetically similar to C57BL/6J also showed a susceptible phenotype. Our phenotypic data suggest that complex genetics underlie FS susceptibility and show that the C57BL/6J strain is highly susceptible to FS. As this strain has been described as resistant to convulsants, our data indicate that susceptibility genes for FS and convulsants are distinct. Insight into the mechanisms underlying seizure susceptibility and FS may help to identify markers for the early diagnosis of children at risk for complex FS and TLE and may provide new leads for treatment.

Background: Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans. Objective: To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system. Results: In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles. Conclusion: Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation.

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