Epileptiform activity has been generally defined, at least at the cellular level, as hyperexcitable and hypersynchronous neuronal discharge. While a seemingly infinite number of underlying factors might contribute to changes in excitability and synchrony, epilepsy research has traditionally focused on abnormalities of intrinsic neuronal properties (e.g., voltage-gated ion channel function) and of synaptic transmission (e.g., changes in receptor numbers, subunit composition, and/or kinetics). There is certainly ample potential within these categories for explaining epileptiform discharge. And there is no question that aberrations in these neuronal features can give rise to epileptic conditions. However, consideration of only these factors significantly over-simplifies the epileptic condition, for the function of neuronal channels and receptors interacts closely with other elements in brain tissue. In particular, there is "obligatory" interplay involving neuronal activity, glial cell function, and blood flow. Many (most) of these interactions are mediated through the extracellular space - so that changes in the extracellular milieu will inevitably have dramatic effects on neuronal excitability and synchrony. A few examples of such interactions are instructive, since they illustrate the specificty of many of these mechanisms. 1 ) Neuronal activity gives rise to changes in extacellular osmolarity - which in turn can affect neuronal excitability. We (with Scott Baraban) have shown that exposing hippocampal slice tissue to hypo-osmolar bathing medium enhances outward potassium currents in a neuron-selective manner. Such effects were seen not only on whole-cell currents, but also in pulled patches -but only on hippocampal interneurons. The enhanced potassium currents were associated, as expected, with a decreased rate of neuronal discharge in affected cells. Since hippocampal interneurons are inhibitory, this hypo-osmolar effect on interneuron potassium currents helps explain the net increase in neuronal excitation observed under these hypo-osmolar conditions. 2) Glial function has long been seen as a basis for regulating the ionic composition of the extracellular space. Recent data, however, suggest that not all astrocytes are alike. Janigro and colleagues (see presentation by Janigro in this symposium) have identified heterogeneous glial populations in hippocampus (and other CNS tissues), and described some of their currents that appear to be critical in regulating neuronal excitability. The glial heterogeneity extends also to glial morphology (worked carried out with Jürgen Wenzel). For example, glial coupling appears quite different in CA1 and CA3 regions of hippocampus, suggesting differential "strategies" used by glia within these sub-regions to "buffer" extracellular ion levels and to establish bridges with the vasculature. Astrocytic end-feet associated with blood vessels, astrocytic processes around synapses, and oligodendroglial association with axonal processes all suggest the critical regulatory roles played by these omnipresent brain elements. 3) Finally, recent studies have suggested that the chloride co-transporter may be an interesting target for the development of antiepileptic medications. Our experiments (with Daryl Hochman) have shown that drugs like furosemide, which block this family of co-transporters (some of which are localized to glia and vascular endothelial cells), can be "antiepileptic" in many laboratory models of epileptiform discharge. This effect can be mimicked by lowering extracellular chloride concentration - a manipulation that results in a desynchronization of neuronal activity but not in blockade of neuronal excitability. We suggest that this effect is a result of extracellular potassium accumulation at axonal branch points, thus impeding high fidelity (i.e., synchronous) transmission of electrical activity from pre- to post-synaptic neurons. These experiments (and the many others to be described in Session 3 of this Symposium) show that neuronal excitability and synchrony can be affected by a large number of interacting influences, involving neurons, glia, vasculature, and extracellular milieu. Although elucidating all these factors makes our jobs vastly more complicated, it also opens a window toward development of novel treatments for epileptic activities.
|Original language||English (US)|
|Number of pages||2|
|Journal||Italian Journal of Neurological Sciences|
|State||Published - 1999|
ASJC Scopus subject areas
- Clinical Neurology