Ion Channel Regulation of Excitability in Immature Brain
The immature brain exhibits a greater propensity for learning and memory than the adult brain, and the mechanisms that underlie this are believed to be a greater potential for synaptic plasticity. The ability to induce synaptic plasticity, or an increase in the efficacy in synaptic communication between a presynaptic terminal and postsynaptic neuron, is greater in young as opposed to adult hippocampus. The underlying mechanism includes an increase in the threshold for plasticity induction in the young compared to the adult brain. Many factors contribute to this developmental regulation, but one of the overriding features appears to be a difference in the balance of excitatory and inhibitory transmission in the hippocampus. Indeed there is a critical period early in development in the rodent hippocampus in which synaptogenesis and neuroplasticity are increased, particularly in the second postnatal week when the receptors for the excitatory amino acid neurotransmitter, glutamate, are highly expressed, and the typically inhibitory neurotransmitter, GABA, has an excitatory effect.
The intrinsic membrane properties of neurons also play an important role in the regulation of excitability in the developing nervous system. Indeed, the electrical properties of neurons during development are thought to be critical to the development of the mature neuronal network. This has been particularly well-characterized in the visual system. Potassium (K+) currents in particular contribute to the maturation of the action potential and firing behavior of neurons. It is now becoming evident that intrinsic membrane properties of neurons are highly dynamic and are regulated by activity. Recent work has begun to elucidate the molecular constituents of these currents that are critical to both developing and adult neurons. One particular class of K + channels, the small conductance Ca 2+ -activated K + (SK) channels have been shown to be an important determinants of the electrical activity and firing behavior of neurons in the developing nervous system. SK channels contribute to the afterhyperpolarization (AHP) current that follows a single or train of action potentials. It is known that Ca 2+ signaling is an important aspect in the maturation of neuronal networks and SK channels are highly regulated by Ca 2+ . Hence, SK channels at least in some regions of the CNS are thought to play a role in this developmental process.
In the studies outlined here we will developmentally characterize the expression of a specific SK channel subunit, SK2 that contributes to the early or medium AHP (mAHP) in hippocampal area CA1. SK2 expression levels will be correlated with the mAHP over development. While a similar correlation has been performed in rat cerebellar Purkinje cells, it has not previously been performed in developing hippocampus. While expression levels of SK2 and the underlying mAHP may influence the intrinsic properties as well as the output of developing CA1 pyramidal neurons, we also propose that regulation of these channels post-translationally through the cAMP-dependent protein kinase (PKA) pathway may play a role in the modulation of SK2 channel function during development. Activity-dependent modulation of signaling pathways is known to influence a number of neuronal functions involved in process outgrowth and differentiation as well as the properties of ion channels.
Relevance of the project to IDDRC mission:
SK2 channel changes during development. This channel affects network activity in certain area of brain and thus is critical to synaptic plasticity and learning and memory. It is known that the expression of an ionic current may have profound effect on synaptic plasticity during development. Hence in studying the developmental regulation of SK2 channel, we can identify the components of the pathway which lead to learning deficits in development under physiological and pathological conditions such as mental retardation and epilepsy.