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Abstract
Neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body. Yet the rules of molecular signal propagation from dendrites to nuclei are unknown. DARPP-32 is a phosphorylation-regulated signalling hub in striatal output neurons. We combine diffusion-reaction modelling and live imaging to investigate cAMP-activated DARPP-32 signalling to the nucleus. The model predicts maximal effects on the nucleus of cAMP production in secondary dendrites, due to segmental decrease of dendrite diameter. Variations in branching, perikaryon size or spines have less pronounced effects. Biosensor kinase activity measurement following cAMP or dopamine uncaging confirms these predictions. Histone 3 phosphorylation, regulated by this pathway, is best stimulated by cAMP released in secondary-like dendrites. Thus, unexpectedly, the efficacy of diffusion-based signalling from dendrites to nucleus is not inversely proportional to the distance. We suggest a general mechanism by which dendritic geometry counterbalances the effect of dendritic distance for signalling to the nucleus.
Highlights
Neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body
To understand the relationship between the dendrite morphology and signalling to the nucleus we focused on cyclic AMP-dependent signalling in striatal medium-size spiny neurons (MSNs), which is activated by several receptors including D1 dopamine receptors (D1R)
We investigated the spatiotemporal dynamics of the pathway involving cyclic AMP (cAMP), cAMP-dependent protein kinase (PKA) and 32-kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32)
Summary
Neurons have complex dendritic trees, receiving numerous inputs at various distances from the cell body. To understand the relationship between the dendrite morphology and signalling to the nucleus we focused on cyclic AMP (cAMP)-dependent signalling in striatal medium-size spiny neurons (MSNs), which is activated by several receptors including D1 dopamine receptors (D1R). It mediates phasic effects of dopamine in action selection, movement control and motivation, and is critical in dysfunctions of the basal ganglia including drug addiction and L-DOPA-induced dyskinesia in Parkinson’s disease[15]. Our results show that dendritic morphology and biochemical properties of signalling pathways shape signalling from synapses to nucleus and can counterbalance the effects of distance These observations result from simple principles likely to have implications for other pathways and neurons
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