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Several neurotransmitters, including GABA acting at presynaptic GABA[subB] receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABA[subB] receptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABA[subB] receptor agonist baclofen. Autoradiography revealed a reduction in GABA[subB] receptor binding in the stratum lucidum after status epilepticus. Failure of GABA[subB] receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus. [ABSTRACT FROM AUTHOR]

Absence epilepsy, a disease predominantly of childhood, has long been known to arise from an aberration of the interplay between two brain regions, the cortex and the thalamus. Pharmacological treatment of the disorder has advanced little during past decades, with ethosuximide and sodium valproate remaining the principle drugs of choice. Absence epilepsy is classified as a generalized seizure type and it has been widely assumed that the thalamus is the generator of this seizure activity. However, recent evidence has identified a specific site of seizure generation within the peri-oral region of the primary somatosensory cortex (S1po). Furthermore, ethosuximide has been shown to exert its inhibitory effect on absence seizure activity specifically at this focus, and not in other parts of the cortex or in the thalamus. A greater understanding of the molecular mechanisms within this cortical region might therefore give rise to newer, more effective treatments of absence epilepsy, and perhaps of other thalamocortical dysfunctions. [Copyright &y& Elsevier]

In the present study, we have investigated GABAB receptor expression in somatosensory cortex (S1) and the ventrobasal (VB) and reticular (Rt) thalamic nuclei of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), which represent an animal model for the human absence epilepsy. We focused our attention on the thalamocortical network because it has been demonstrated that absence seizures are generated in this specific circuit, which is under the control of several inhibitory, e.g. GABA, and excitatory systems.Autoradiography data obtained with the GABAB receptor antagonist [3H]CGP62349 did not show any differences in Kd or Bmax values between control rats and GAERS. In situ hybridisation (ISH) results showed a significant increase in messenger RNA for GABAB1 in the S1 and a decrease in the VB thalamic nucleus but not in the Rt thalamic nucleus. By contrast the immunocytochemical data revealed an increased expression of both GABAB1 and GABAB2 receptor subunits in all the regions examined, somatosensory cerebral cortex, VB thalamus and Rt nucleus in GAERS compared to controls.The main finding was an up-regulation of GABAB receptor protein in the corticothalamic circuit in GAERS compared to controls. [Copyright &y& Elsevier]

Absence epilepsy is characterised by recurrent periods of physical and mental inactivity coupled to bilateral, synchronous spike and wave discharges (SWDs) on the electroencephalogram. The mechanism of action of ethosuximide (ETX), a drug specific for absence seizures, is believed to involve a reduction in the low threshold T-type Ca2+ current in thalamocortical and nucleus reticularis thalami (NRT) neurones, although other electrophysiological data have questioned this. Here, we employed a genetic rat model of absence seizures to investigate the effects of directly administering ETX to the thalamus.SWDs were immediately and substantially reduced (∼90%) by systemic administration of ETX (177–709 μmol/kg), or by bilateral microinfusion into the thalamus of the GABAB antagonist, CGP 36742 (5–27 nmol per side). However, infusion of ETX (1–200 nmol per side) into the ventrobasal complex or the NRT resulted in a reduction of SWDs that was delayed (30–60 min) and less marked (∼50%). Administration of ETX (0.2 mM to 1 M) to a greater volume of thalamus by reverse microdialysis also produced significant but delayed reduction of SWDs at concentrations >1 mM. Only at 5 mM were seizures significantly reduced (∼70%) within 30 min of administration.These results suggest that targeting of the thalamus alone may be insufficient for an immediate and full anti-absence action for ETX. Concomitant or exclusive actions in the cortex remain a possibility. [Copyright &y& Elsevier]