The Laboratory of Neurobiology pursues two main lines of research:
1) The most fundamental mechanisms of neuronal signaling are based on movements of ions across the plasma membrane via channels and ion transporters. We are studying the functions of ion-regulatory proteins (IRPs), such as cation-chloride cotransporters (CCCs) and carbonic anhydrases (CAs), in the control of neuronal development, signaling and disease at the molecular, single-cell and network levels.
When compared to ion channels, IRPs have received much less attention in neurobiological research, but this biased situation is undergoing a profound change that started about a decade ago (see more at the “Milestones” page). In addition to ion regulation, some IRPs also serve as structural elements in neuronal morphogenesis. Because of their multifunctional characteristics, IRPs are involved in diverse brain functions and disorders.
2) Birth asphyxia
Mammalian birth is always accompanied by a period of obligatory asphyxia during the transition from placental to lung-based breathing. During complicated birth, the duration of the asphyxia is prolonged, leading to a pathophysiological state which is diagnosed as clinical birth asphyxia. This, in turn, is a main cause of neonatal hypoxic-ischemic encephalopathy. Our laboratory is studying the molecular, cellular and network mechanisms underlying the physiological and pathophysiological responses to birth asphyxia in rodents and in human neonates. Our focus is on neuroendocrine signaling based on arginine vasopressin (AVP), and on monitoring changes in brain pH as well as O2 and CO2 levels in order to develop effective means for post-asphyxia resuscitation.
1. KCC2 transporter function during early development
KCC2 is the main K-Cl cotransporter in central neurons and, as originally shown by our laboratory, it is responsible for the “classical”, Eccles-type hyperpolarizing postsynaptic (as well as extrasynaptic) responses evoked by GABA and glycine. KCC2 is strongly upregulated during the second postnatal week in cortical structures in the rat and mouse. However, using specific pharmacological targeting, we have recently discovered that KCC2 mediates Cl- extrusion in hippocampal neurons much earlier than previously believed. (1, 2)
2. KCC2 in the generation of dendritic spines
KCC2 has a dual role in that it acts as a K-Cl cotransporter, and also as a structural protein in neurons. According to our recent data, the morphogenetic role of KCC2 in the development of dendritic spines in vivomight be totally independent from its transporter function. We are currently using super-resolution imaging among other techniques to study the subcellular distribution of functionally distinct pools of KCC2 molecules. (3)
3. KCC2 in neuronal migration
A third function of KCC2 is currently emerging: We have found that in mice, loss of KCC2 during early cortical development affects the migration of cortical pyramidal neurons in a manner independent of its K-Cl cotransport function. As the main approach, we manipulate KCC2 expression levels in neuronal subpopulations using in uteroelectroporation.
4. KCC2 mutations associated with human epilepsy
Because of its crucial roles in various neuronal functions (see above), it is not surprising that KCC2 mutations are rare. Having discovered the first disease related KCC2 mutation, we are now working on the properties of two other point mutations, which have been identified in patients with epileptic phenotype. (2)
5. Developmental expression patterns of NKCC1
The Na-K-2Cl cotransporter is expressed in most cell types, and in neurons it acts as the main uptake mechanism for Cl-. As a whole, publications dealing with the developmental regulation of NKCC1 are highly contradictory. Currently, we are using cell-type specific detection of NKCC1 to analyze its spatiotemporal expression patterns at distinct developmental stages of the cortex. (2)
6. Carbonic anhydrase isoform 7 (CA7)
We showed originally that depolarizing and excitatory currents are carried by HCO3-across GABAA receptors in mature CNS neurons. In this kind of GABAergic excitation, intraneuronal CA is responsible for fast replenishment of bicarbonate. CA7 was first identified as a neuron-specific isoform by our team, and we are currently examining its role in morphofunctional plasticity. Using CA7 deficient mice enables us to specifically study the effects of CA7 on dendritic spine morphology and on neuronal excitability and seizure susceptibility. (1, 4, 5)
1. Pathophysiological, adaptive and endocrine mechanisms in birth asphyxia
The transition from placental to lung-based breathing during birth is accompanied by an obligatory period of asphyxia in all mammals. Powerful mechanisms have evolved to protect the fetus from asphyxia, but their capacity can be exceeded in complicated birth, leading to neuronal injury. We are currently studying the neuroprotective role of arginine vasopressin (AVP) and the molecular, cellular, and network mechanisms underlying the pathological responses to birth asphyxia and their behavioral consequences using rodent models. Our aim is to develop novel therapeutic strategies for asphyxia including resuscitation with elevated CO2in the inspired air. (6-10)
2. Copeptin, a part of prepro-AVP, as a biomarker of birth asphyxia
We have recently shown in retrospective studies that blood copeptin, a biochemically stable part of the prepro-AVP that is released into the blood, is a promising diagnostic and prognostic biomarker of birth asphyxia and its long-term outcome. A prospective study is ongoing with Dr. Geraldine Boylan from University College Cork in Ireland. (7)