Abstract
Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not known if these channels regulate the spatiotemporal spread of signaling microdomains. Here, we employed a multiscale, morphologically realistic, conductance-based model of the hippocampal pyramidal neuron that accounted for experimental details of electrical and calcium-dependent biochemical signaling. We activated synaptic N-Methyl-d-Aspartate receptors through theta-burst stimulation (TBS) or pairing (TBP) and assessed microdomain propagation along a signaling pathway that included calmodulin, calcium/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1. We found that the spatiotemporal spread of the TBS-evoked microdomain in phosphorylated CaMKII (pCaMKII) was amplified in comparison to that of the corresponding calcium microdomain. Next, we assessed the role of two dendritically expressed inactivating channels, one restorative (A-type potassium) and another regenerative (T-type calcium), by systematically varying their conductances. Whereas A-type potassium channels suppressed the spread of pCaMKII microdomains by altering the voltage response to TBS, T-type calcium channels enhanced this spread by modulating TBS-induced calcium influx without changing the voltage. Finally, we explored cross-dependencies of these channels with other model components, and demonstrated the heavy mutual interdependence of several biophysical and biochemical properties in regulating microdomains and their spread. Our conclusions unveil a pivotal role for dendritic voltage-gated ion channels in actively amplifying or suppressing biochemical signals and their spatiotemporal spread, with critical implications for clustered synaptic plasticity, robust information transfer and efficient neural coding.
Highlights
Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in defining several neuronal computations, including compartmentalization of neuronal plasticity and localized targeting of membrane components [1,2,3,4,5,6,7,8,9,10]
From a physiological standpoint, the spread of the calmodulin-dependent protein kinase II (CaMKII) microdomain in this signaling pathway directly translates to the spread of neuronal plasticity through phosphorylation of several substrates that include 2-amino-3-(5-methyl3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors and several ion channels [4,42,43,51, 52,56,62]
As would be expected from the binding kinetics of the reactions, and especially by the autophosphorylation of CaMKII, there was an increase in the spatiotemporal spread of the microdomain associated with phosphorylated CaMKII (pCaMKII) compared to that of calcium. These results quantitatively demonstrate that theta-burst stimulation (TBS) induces localized calcium influx, which, through propagation along an established signaling pathway, results in a microdomain of pCaMKII with a spread larger than that of the calcium microdomain [41,43,47]
Summary
Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in defining several neuronal computations, including compartmentalization of neuronal plasticity and localized targeting of membrane components [1,2,3,4,5,6,7,8,9,10]. Neuronal electrical signaling and physiology, is defined by the presence and plasticity of voltage-gated ion channel conductances, some of which are present at higher densities in the dendrites than at the cell body [9,12,13,14,15,16,17,18,19,20,21,22,23,24] Consequent to their ability to significantly alter calcium influx into neuronal compartments, these active dendritic conductances are well established as critical regulators of synaptic plasticity profiles [12,13,14,19,25,26,27,28,29,30,31,32,33,34,35]. Upon stimulation with such randomized background activity, the mean somatic RMP was found to be –64.33 mV ± 0.74 mV (Fig 10A)
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