Laboratory of Neurobiology

Our research has focused on the role of ion-regulatory proteins in the control of neuronal excitability at the molecular, single-cell, network and in vivo levels.

(1) We have identified the first human KCC2 mutation. This missense variant is a susceptibility gene for febrile seizures and perhaps other seizure disorders.

(2) A novel project has been started focusing on the role of the HPA axis on brain pH regulation and neuronal excitability. This work aims at elucidating the molecular mechanisms underlying birth-asphyxia seizures and brain trauma.

(3) The neuronal chloride extruder KCC2, a key molecule in GABAergic inhibition, upregulated following neonatal seizures, which is opposite to seizure effects in the mature brain. Our work points to age-dependent differences in the effects of neurotrophic factors on the trafficking of KCC2.

(4) The neuronal carbonic anhydrase isoform 7 (CA7) has turned out to be a key molecule in seizure generation and a promising anticonvulsant drug target. Using a novel CA7 KO, as well as CA2 KO and double CA7/CA2 KO mice, we have examined the roles of these isoforms in neuronal pH regulation and in the establishment of excitatory bicarbonate-dependent GABA responses during hippocampal development.

(5) Experimental febrile seizures (FS) cannot be evoked in the CA7 KO mice. The lack of FS is likely to be caused by a change in neuronal pH responsiveness, and not due to an absence of hyperthermia-induced hyperventilation.

(6) We have shown that 5% CO2 is a potent anticonvulsant in animal models and human epilepsy patients.

(7) We have developed a novel rodent model of birth asphyxia. Two-photon pH imaging in vivo as well as extracellular pH recordings have shown that birth asphyxia leads to a rise in both intra- and extracellular pH in the brain. The experimental birth-asphyxia seizures can be suppressed by preventing the fast rise in brain pH during recovery. A retrospective clinical study is in progress.

(8) Using specific ablation of the cortical subplate in neonatal rats, we have examined activity-dependent structural and functional (EEG) development of the neocortex.