Research Groups - Physiology
Neuronal development, plasticity and hyperexcitability: biophysical, molecular and cellular mechanisms
PhD, Professor Kai Kaila
Neuronal development, plasticity and hyperexcitability: biophysical, molecular and cellular mechanisms
GABAergic signaling has the unique property of "ionic plasticity". This is based on short-term and long-term changes in
the transmembrane gradients of Cl- and HCO3-. While short-term ionic plasticity is caused by activity-dependent,
channel-mediated changes in the intracellular concentrations of these two anions, long-term ionic plasticity depends on
changes in the expression patterns of proteins involved in the regulation of intraneuronal anions.
During neuronal development, both the qualitative nature (depolarization/excitation vs. hyperpolarization/inhibition)
as well as the efficacy of GABAergic transmission is governed by two major anion-regulatory molecules: the chloride-
extruding K-Cl cotransporter KCC2, and the intraneuronal carbonic anhydrase (CA) isoform, CAVII.
In rat hippocampal pyramidal neurons, a steep up-regulation of KCC2 expression that closely parallels synaptogenesis is
seen during the first two weeks after birth. This accounts for the "developmental switch", which converts depolarizing
and excitatory GABA responses of immature neurons to classical hyperpolarizing IPSPs. At around postnatal day 12 (P12),
an abrupt, steep increase in CAVII expression takes place. The intraneuronal carbonic anhydrase activity promotes
bicarbonate-dependent excitatory and often epileptiform responses during intense GABAergic activity. For instance, high-
frequency stimulation of GABAergic neurons in hippocampal slices at P12 and later leads to spatially widespread
neuronal depolarization associated with population spike activity in the gamma-frequency range. CAVII may be a major
target of carbonic anhydrase inhibitors that are widely used as antiepileptic drugs.
The early postnatal rat hippocampus generates large-scale network activity, seen as GDPs ("giant depolarizing
potential") in intracellular recordings. The abolishment of GDPs during neuronal maturation is linked to an up-
regulation of KCC2. In human preterms (conceptual age 33-40 week), DC-EEG reveals large-scale, spontaneous activity
transients (SATs) in the immature neocortex. In situ hybridization in age-matched human fetal cortical tissue shows
that the disappearance of SATs during cortical maturation is, again, paralleled by
up-regulation of KCC2.
KCC2 expression in adult rat neurons is down-regulated in an activity-dependent manner by BDNF/trkB signaling, and
preliminary evidence suggests that CAVII expression is also influenced by neurotrophic factors. The lifetime of
membrane-associated KCC2 is very short, in the range of tens of minutes, which makes KCC2 ideally suited for mediating
GABAergic ionic plasticity. In addition, factors influencing the trafficking and kinetic modulation of KCC2 as well as
activation/deactivation of CAVII are obvious candidates in the ionic modulation of GABAergic responses. Finally, the
down-regulation of KCC2 and CAVII under pathophysiological conditions (epilepsy, damage) in mature neurons seems to
reflect as "recapitulation" of early developmental mechanisms, which may be a prerequisite for the re-establishment of
connectivity in damaged brain tissue.
Project's own website: http://www.helsinki.fi/neurobiology/
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