Dopaminergic tone persistently regulates voltage-gated ion current densities through the D1R-PKA axis, RNA polymerase II transcription, RNAi, mTORC1, and translation

Abstract

Long-term intrinsic and synaptic plasticity must be coordinated to ensure stability and flexibility in neuronal circuits. Coordination might be achieved through shared transduction components. Dopamine (DA) is a well-established participant in many forms of long-term synaptic plasticity. Recent work indicates that DA is also involved in both activity-dependent and -independent forms of long-term intrinsic plasticity. We previously examined DA-enabled long-term intrinsic plasticity in a single identified neuron. The lateral pyloric (LP) neuron is a component of the pyloric network in the crustacean stomatogastric nervous system (STNS). LP expresses type 1 DA receptors (D1Rs). A 1 h bath application of 5 nM DA followed by washout produced a significant increase in the maximal conductance (Gmax) of the LP transient potassium current (IA) that peaked ~4 h after the start of DA application; furthermore, if a change in neuronal activity accompanied the DA application, then a persistent increase in the LP hyperpolarization activated current (Ih) was also observed. Here, we repeated these experiments with pharmacological and peptide inhibitors to determine the cellular processes and signaling proteins involved. We discovered that the persistent, DA-induced activity-independent (IA) and activity-dependent (Ih) changes in ionic conductances depended upon many of the same elements that enable long-term synaptic plasticity, including: the D1R-protein kinase A (PKA) axis, RNA polymerase II transcription, RNA interference (RNAi), and mechanistic target of rapamycin (mTOR)-dependent translation. We interpret the data to mean that increasing the tonic DA concentration enhances expression of a microRNA(s) (miRs), resulting in increased cap-dependent translation of an unidentified protein(s).

Modulation of a Single Neuron Has State-Dependent Actions on Circuit Dynamics

“…Additionally, some neuromodulatory actions are contingent on the presence of other modulators, or recent history of neuromodulation, often with significant behavioral consequences (Dickinson et al, 1997; Nadim et al, 2008; Chalasani et al, 2010; Wu et al, 2010; Rodgers et al, 2011a, 2011b; Jang et al, 2012; Kwiatkowski et al, 2013; Krenz et al, 2014; Nadim and Bucher, 2014). In principle, the action of any given neuromodulator on a circuit can be restricted to a few circuit elements, or can be more widespread.…”

Spatial distribution of intermingling pools of projection neurons with distinct targets: A 3D analysis of the commissural ganglia in Cancer borealis

“…The advent of new genetic and molecular tools (Clark, Khan, & Baro, 2008;Garcia, Daur, Temporal, Schulz, & Bucher, 2015;Krenz, Parker, Rodgers, & Baro, 2014;Moroz et al, 2008;Schulz, Goaillard, & Marder, 2007;Temporal, Lett, & Schulz, 2014) will further allow testing this concept by determining genetic cell identities and the cellular distribution of receptors and ion channels. Our study supports that this concept also applies to anatomical structures.…”

Homeostatic plasticity of excitability in crustacean central pattern generator networks

“…These findings demonstrate a mechanism by which modulation can provide flexibility and stability through a self-stabilizing feedback loop to maintain the I A :I H ratio, and that low levels of constitutive modulation can potentiate activity-dependent regulation of conductances [35]. Interestingly, these high-affinity D1 receptors also act on longer timescales to increase both of these ionic conductances through pathways that depend on transcription, translation, and RNA interference [36,37]. Similarly, new evidence implicates tonic nanomolar concentrations of other amines in regulating I A and I H in PD neurons, suggesting cell-type specific regulation [38] which occurs in part through tonic levels of modulation influencing expression of microRNAs [37,38].…”

“…While neuromodulation can influence longer-term expression of channels in STG neurons (see above; [35–37,40]), only recently has there been evidence of direct activity-dependent feedback to the level of channel mRNAs. Temporal et al [46] recently performed such a study that decoupled the effects of loss of activity and neuromodulation as a result of decentralization of STG neurons (Figure 3D).…”