Model of Clustering of Ca-Channels Deduced From the Kinetics of BK Currents in Dopamine Neurons During Development

Many connections between key areas of the basal ganglia are made around birth when animals are exposed to a host of new affective, cognitive, and sensori-motor stimuli, for which the animals have to make neuronal connections in order to respond to these stimuli appropriately. Dopamine (DA) plays a role in this process by modulating cortico-striatal synapses that result in strengthening of connections that lead to desired outcomes [1]. During the first days of postnatal development, we observe that rat dopamine neurons are electrically immature and would not support the release of DA underlying the modulation of striatal synapses. On DA neurons, calcium-activated K+ channels of two types, SK and BK, are upregulated rapidly after birth and organize around specific types of Ca channels on at least two different kinds of geometrical clusters. These clusters are necessary for the proper function of BK channels. We present a mathematical model where we infer the size of the clusters based on the kinetics of the BK currents. We solve the diffusion equation for Ca+2 and buffers using finite elements. In the first cluster T-type Ca-channels are tightly coupled to BK channels with space constant of less than 20nm. The second cluster consists of L-type Ca-channels and is spread over a distance of at least 60 nm. These two geometrical arrangements are necessary to generate the Ca+2 currents that can reproduce the kinetics of inactivating and non-inactivating BK currents. We discuss the implications of this model for the functional development of the basal ganglia.

Keywords: dopamine, BK-Channels, Ca-Channels, Diffusion, BasalGanglia, Parkinson