K-ATP Channels in Dopamine Substantia Nigra Neurons Control Bursting and Novelty-induced Exploration

Phasic activation of the dopamine (DA) midbrain system in response to unexpected reward or novelty is critical for adaptive behavioral strategies. This activation of DA midbrain neurons occurs via a synaptically triggered switch from low-frequency background spiking to transient high-frequency burst firing. We found that, in medial DA neurons of the substantia nigra (SN), activity of ATP-sensitive potassium (K-ATP) channels enabled NMDA-mediated bursting in vitro as well as spontaneous in vivo burst firing in anesthetized mice.

Cell-selective silencing of K-ATP channel activity in medial SN DA neurons revealed that their K-ATP channel–gated burst firing was crucial for novelty-dependent exploratory behavior. We also detected a transcriptional upregulation of K-ATP channel and NMDA receptor subunits, as well as high in vivo burst firing, in surviving SN DA neurons from Parkinson's disease patients, suggesting that burst-gating K-ATP channel function in DA neurons affects phenotypes in both disease and health.

Laser microdissection plays a key role in these examinations. Besides electrophysiological measurements of signals in single neurons, the contents of the neurons can be sucked, enabling molecular biological analysis to be acquired as well as electrophysiological data. However, this process is very time-consuming and restricted to laboratory animals.

Using laser microdissection it is possible to collect a large number of single cells, analyze their molecular composition and compare them with cells whose contents have been sucked after electrophysiological measurements. This means that cells “of the same content” are indirectly assignable to the same signals. This step can also be extended further to human post-mortem single cells that can only be collected specifically from certain sub-regions by laser microdissection. In this paper, murine and human dopaminergic neurons were used for analysis, allowing conclusions to be drawn on human pathomechanisms. 



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