Abstract
Volume transmission results in phasic and tonic modulatory signals. The actions of tonic dopamine (DA) at type 1 DA receptors (D1Rs) are largely undefined. Here we show that tonic 5nM DA acts at D1Rs to stabilize neuronal output over minutes by enabling activity-dependent regulation of the hyperpolarization activated current (I h). In the presence but not absence of 5nM DA, I h maximal conductance (G max) was adjusted according to changes in slow wave activity in order to maintain spike timing. Our study on the lateral pyloric neuron (LP), which undergoes rhythmic oscillations in membrane potential with depolarized plateaus, demonstrated that incremental, bi-directional changes in plateau duration produced corresponding alterations in LP I hG max when preparations were superfused with saline containing 5nM DA. However, when preparations were superfused with saline alone there was no linear correlation between LP I hGmax and duty cycle. Thus, tonic nM DA modulated the capacity for activity to modulate LP I h G max; this exemplifies metamodulation (modulation of modulation). Pretreatment with the Ca2+-chelator, BAPTA, or the specific PKA inhibitor, PKI, prevented all changes in LP I h in 5nM DA. Calcineurin inhibitors blocked activity-dependent changes enabled by DA and revealed a PKA-mediated, activity-independent enhancement of LP I hG max. These data suggested that tonic 5nM DA produced two simultaneous, PKA-dependent effects: a direct increase in LP I h G max and a priming event that permitted calcineurin regulation of LP I h. The latter produced graded reductions in LP I hG max with increasing duty cycles. We also demonstrated that this metamodulation preserved the timing of LP’s first spike when network output was perturbed with bath-applied 4AP. In sum, 5nM DA permits slow wave activity to provide feedback that maintains spike timing, suggesting that one function of low-level, tonic modulation is to stabilize specific features of a dynamic output.
Highlights
Homeostatic mechanisms stabilize neuronal firing patterns [1]
In order to further examine the function of tonic nM DA, we performed experiments wherein the STNS was dissected out, pinned in a dish and constantly superfused to prevent the accumulation of tonic modulators; 5nM DA was added back to the superfusate (Fig. 1A). In this manuscript we examined the effects of tonic DA on lateral pyloric neuron (LP) Ih, where LP Ih was measured with a standard two-electrode voltage clamp (TEVC) protocol (Fig. 1D)
The main finding of the work presented here is that tonic 5nM DA enables activity-dependent regulation of LP Ih Gmax to stabilize the timing of LP activity
Summary
Hyperpolarization activated, cyclic nucleotide gated (HCN) channels that mediate Ih are often the target of such mechanisms because of their wide-ranging influence on synaptic integration and neuronal excitability [2,3,4,5]. Cognitive impairment associated with Fragile X Syndrome [16] and the loss of pacemaking in Parkinson’s disease [17] can be linked to improper homeostatic regulation of Ih. HCN channels influence several activity features that shape neuronal excitability and synaptic integration including membrane potential, firing threshold, resonance frequency, temporal summation and synaptic strength [5,18,19,20]. Kv4 channels that mediate the transient potassium current (IA) co-vary with HCN channels to maintain the timing of neuronal activity [14,15,25]
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