Neuromodulator-evoked synaptic metaplasticity within a central pattern generator network

Abstract

Synapses show short-term activity-dependent dynamics that alter the strength of neuronal interactions. This synaptic plasticity can be tuned by neuromodulation as a form of metaplasticity. We examined neuromodulator-induced metaplasticity at a graded chemical synapse in a model central pattern generator (CPG), the pyloric network of the spiny lobster stomatogastric ganglion. Dopamine, serotonin, and octopamine each produce a unique motor pattern from the pyloric network, partially through their modulation of synaptic strength in the network. We characterized synaptic depression and its amine modulation at the graded synapse from the pyloric dilator neuron to the lateral pyloric neuron (PD→LP synapse), driving the PD neuron with both long square pulses and trains of realistic waveforms over a range of presynaptic voltages. We found that the three amines can differentially affect the amplitude of graded synaptic transmission independently of the synaptic dynamics. Low concentrations of dopamine had weak and variable effects on the strength of the graded inhibitory postsynaptic potentials (gIPSPs) but reliably accelerated the onset of synaptic depression and recovery from depression independently of gIPSP amplitude. Octopamine enhanced gIPSP amplitude but decreased the amount of synaptic depression; it slowed the onset of depression and accelerated its recovery during square pulse stimulation. Serotonin reduced gIPSP amplitude but increased the amount of synaptic depression and accelerated the onset of depression. These results suggest that amine-induced metaplasticity at graded chemical synapses can alter the parameters of synaptic dynamics in multiple and independent ways.

Fig. 1.

Synaptic dynamics of graded synaptic transmission at the PD→LP chemical synapse. A: lateral pyloric (LP) graded inhibitory postsynaptic potentials (gIPSPs) in response to 3-s pyloric dilator (PD) neuron square pulse depolarizations. Initial peak and steady-state IPSP amplitudes and the time constant for synaptic depression (τ_Dep) were measured for all PD depolarizations from a holding potential (V_hold) of −55 mV. B: LP gIPSPs during a train of 12 realistic PD oscillations of increasing amplitude from V_hold = −55 mV. The first gIPSP amplitude (initial peak) and the mean of the last 5 gIPSPs amplitudes (steady state) were measured for all PD depolarizations. C: mean input/output relationship for the amplitude of the initial peak (open circles) and steady-state (open squares) gIPSPs during square pulse PD stimulation (n = 11). D: mean input/output relationship for initial (filled circles) and steady-state (filled squares) LP gIPSP amplitudes during PD oscillation stimulation (n = 7). E: mean depression index (DI) for square pulse (open bars) and oscillation (filled bars) stimulation across PD stimulation voltages. *Significantly greater DI for PD square pulse stimulation than for PD oscillation stimulation (P < 0.001 for all PD voltages). The DI did not show voltage dependence with either stimulation protocol (P > 0.20 for both).

Fig. 2.

Synaptic depression and recovery at the PD→LP graded synapse. A: mean τ_Dep across PD square pulse stimulation voltages (n = 11). τ_Dep did not show any voltage dependence (P = 0.95). B: measurement of the time constant of LP gIPSP recovery from depression (τ_Rec) in response to PD square pulse depolarization to −25 mV. C: measurement of τ_Rec in response to PD oscillation depolarization to −25 mV. D: mean τ_Rec for LP gIPSPs elicited by PD square pulse (n = 13) and oscillation stimulation (n = 10). *Significantly longer τ_Rec with PD oscillation stimulation (P = 0.003).

Fig. 3.

Dopamine (DA; 10⁻⁵ M) modulation of synaptic strength at the PD→LP synapse. A–C: examples showing variable effects of DA to reversibly enhance (A), reduce (B), or have no effect (C) on the initial LP gIPSP amplitude with PD square pulse stimulation. D: mean effects of DA on amplitudes of initial peak and steady-state LP gIPSPs elicited by PD square pulse (open bars, initial peak; light gray bars, steady state) and oscillation stimulation (solid bars, initial peak; dark gray bars, steady state) at −25-mV PD depolarization. E: example showing DA enhancement of the initial peak gIPSP during PD oscillation stimulation. Ctl, control.

Fig. 4.

Dopamine acceleration of synaptic depression and recovery at the PD→LP synapse. A: mean effects of DA on τ_Dep (left, open bars; n = 5) and τ_Rec (middle, open bars; n = 5) during PD square pulse stimulation and on τ_Rec during PD oscillation stimulation (right, filled bars; n = 4). *Significantly shorter τ in DA compared with control conditions (P < 0.005 for all). B: example showing more rapid recovery of gIPSP amplitude during DA after a 1-s interval following PD oscillation stimuli and no effect of DA on the initial peak gIPSP. Gray horizontal lines mark the amplitude of the initial peak gIPSP. C: lack of correlation between DA effects on initial peak LP gIPSP and its effects on depression and recovery in individual experiments. τ_RecSq, τ_Rec for PD square pulse stimulation; τ_RecOsc, τ_Rec for PD oscillation stimulation.

Fig. 5.

Octopamine (10⁻⁵ M) enhances synaptic strength and reduces synaptic depression at the PD→LP synapse. A and B: examples showing Oct enhancement of initial peak and steady-state gIPSP amplitudes during PD square pulse (A) and oscillation stimulation (B). Black traces, control conditions; gray traces, Oct condition. C: Oct enhances mean absolute amplitudes of initial peak and steady-state LP gIPSPs elicited by PD square pulse (open bars, initial peak; light gray bars, steady state; n = 5) and oscillation stimulation (filled bars, initial peak; dark gray bars, steady state; n = 4) at −25-mV PD depolarization. *Significant increase (P < 0.004 for all). #Significantly less Oct enhancement of the initial peak gIPSP amplitude than the steady-state gIPSP amplitude during PD square pulse stimulation (P = 0.04). D: Oct significantly decreases synaptic depression with PD square pulse but not with oscillation stimulation at −25-mV PD depolarization. *Significant reduction (P < 0.0001).

Fig. 6.

Octopamine modulation of synaptic depression and recovery at the PD→LP synapse. A: Oct increases τ_Dep (left, n = 5) and decreases τ_Rec (right, n = 4) at −25-mV PD square pulse depolarization. *Significant effects (P < 0.03 for both). B: example using PD square pulse depolarizations of differing amplitudes to adjust the LP gIPSP to the same amplitude under control and Oct conditions, showing the Oct-induced increase in τ_Dep in size-matched LP gIPSPs (black traces, control; gray trace, Oct). C: example of normalized initial peak gIPSPs in control (black traces) and Oct (gray traces), with more rapid gIPSP recovery in Oct during PD square pulse depolarizations to −25 mV.

Fig. 7.

Serotonin (5-HT; 10⁻⁵ M) decreases synaptic strength and enhances synaptic depression at the PD→LP synapse. A and B: examples showing 5-HT reduction of initial peak and steady-state gIPSP amplitudes during PD square pulse (A) and oscillation stimulation (B). Black traces, control conditions; gray traces, 5-HT. C: 5-HT reduces the amplitudes of initial peak and steady-state LP gIPSPs elicited by PD square pulse (open bars, initial peak; light gray bars, steady state; n = 4) and oscillation stimulation (filled bars, initial peak; dark gray bars, steady state; n = 6) at −25-mV PD depolarization. *Significant at P < 0.005 for both stimulation protocols. D: 5-HT increases synaptic depression. *Significant at P < 0.004 for both stimulation protocols.

Fig. 8.

Serotonin modulation of kinetics of synaptic depression and recovery at the PD→LP synapse. A: 5-HT reduces τ_Dep (left, open bars; n = 4) and has only weak effects on τ_Rec (middle, open bars; n = 3) during −25-mV PD square pulse depolarization and on τ_Rec (right, closed bars; n = 5) during −25-mV PD oscillation depolarization. *Significant effect (P = 0.002). B: example with PD square pulse depolarizations adjusted in control and 5-HT conditions to show the 5-HT-induced acceleration of τ_Dep in size-matched LP gIPSPs (black traces, control; gray traces, 5-HT). C: example showing normalized initial peak gIPSPs in control (black traces) and 5-HT (gray traces) and more rapid gIPSP recovery in 5-HT 1 s after the end of PD oscillations. Gray horizontal lines mark the amplitudes of initial peak gIPSPs.