Functional Upregulation of Ca2+ -Activated K+ Channels in the Development of Substantia Nigra Dopamine Neurons

Abstract

Many connections in the basal ganglia are made around birth when animals are exposed to a host of new affective, cognitive, and sensori-motor stimuli. It is thought that dopamine modulates cortico-striatal synapses that result in the strengthening of those connections that lead to desired outcomes. We propose that there must be a time before which stimuli cannot be processed into functional connections, otherwise it would imply an effective link between stimulus, response, and reward in uterus. Consistent with these ideas, we present evidence that early in development dopamine neurons are electrically immature and do not produce high-frequency firing in response to salient stimuli. We ask first, what makes dopamine neurons immature? and second, what are the implications of this immaturity for the basal ganglia? As an answer to the first question, we find that at birth the outward current is small (3nS-V), insensitive to , TEA, BK, and SK blockers. Rapidly after birth, the outward current increases to 15nS-V and becomes sensitive to , TEA, BK, and SK blockers. We make a detailed analysis of the kinetics of the components of the outward currents and produce a model for BK and SK channels that we use to reproduce the outward current, and to infer the geometrical arrangement of BK and channels in clusters. In the first cluster, T-type and BK channels are coupled within distances of 20 nm (200 Å). The second cluster consists of L-type and BK channels that are spread over distances of at least 60 nm. As for the second question, we propose that early in development, the mechanism of action selection is in a “locked-in” state that would prevent dopamine neurons from reinforcing cortico-striatal synapses that do not have a functional experiential-based value.

BK Channels in the Central Nervous System

“…BK α expression is upregulated during late embryonic and early postnatal development throughout the CNS (Hafidi, Beurg, & Dulon, 2005; Higgins et al, 2010; MacDonald, Ruth, Knaus, & Shipston, 2006). Consistent with this observation, BK currents undergo an abrupt increase during the first 2 weeks after birth in neocortical pyramidal neurons, substantia nigra dopamine neurons, and cochlear inner hair cells (Kang, Huguenard, & Prince, 1996; Kros, Ruppersberg, & Rusch, 1998; Langer, Grunder, & Rusch, 2003; Marcotti, Johnson, Holley, & Kros, 2003; Ramirez-Latorre, 2012). Interestingly, the emergence of BK currents in these cells coincides with their functional maturation, as characterized by increased excitability in the neocortex, high-frequency firing in response to salient stimuli in the substantia nigra, and auditory signal transduction in the cochlea.…”

Specific needs of dopamine neurons for stimulation in order to survive: implication for Parkinson disease

“…Consistent with its pharmacological profile, APA had a protective effect that was blocked by TTX and potentiated by suboptimal concentrations of the Na v channel agonist veratridine (12). CTX a scorpion venom peptide that blocks large‐conductance Ca 2+ ‐activated K + channels (19, 20) also protected DA neurons in midbrain cultures (13). Of interest, these data further reinforce the biological relevance of the culture model, since the presence of functional Ca 2+ activated K + channels is an index of the maturation of DA neurons (20).…”

“…CTX a scorpion venom peptide that blocks large‐conductance Ca 2+ ‐activated K + channels (19, 20) also protected DA neurons in midbrain cultures (13). Of interest, these data further reinforce the biological relevance of the culture model, since the presence of functional Ca 2+ activated K + channels is an index of the maturation of DA neurons (20). Tertiapin‐Q, a bee venom component that depolarizes DA neurons by specifically blocking protein‐gated inwardly rectifying K + (GIRK) channels (21), increased the number of neurons expressing the rate‐limiting enzyme of dopamine synthesis, tyrosine hydroxylase (TH), in midbrain cultures (22).…”

Short Review of Ischemia- and Hypoxia-Protective Roles of “Big Potassium” (BK) Channels

“…And the expression of particular BK subunit subtypes tune the BK channels to the local signaling environment (unless otherwise specified, we will use the term to mean Journal of Biosciences and Medicines functional expression of these channels. BK channel currents abruptly increase during the first two weeks after birth in animal models [16], which may be coincident with their functional maturation as the channels adjust (to) neuronal properties as the animal matures. This is an "experience dependent plasticity" that helps shape how BK channels will function in the mature animal [15] [17].…”