Synaptic depression creates a switch that controls the frequency of an oscillatory circuit

Abstract

Synaptic depression is a form of short-term plasticity exhibited by many synapses. Nonetheless, the functional significance of synaptic depression in oscillatory networks is not well understood. We show that, in a recurrent inhibitory network that includes an intrinsic oscillator, synaptic depression can give rise to two distinct modes of network operation. When the maximal conductance of the depressing synapse is small, the oscillation period is determined by the oscillator component. Increasing the maximal conductance beyond a threshold value activates a positive-feedback mechanism that greatly enhances the synaptic strength. In this mode, the oscillation period is determined by the strength and dynamics of the depressing synapse. Because of the regenerative nature of the feedback mechanism, the circuit can be switched from one mode of operation to another by a very small change in the maximal conductance of the depressing synapse. Our model was inspired by experimental work on the pyloric network of the lobster. The pyloric network produces a simple motor rhythm generated by a pacemaker neuron that receives feedback inhibition from a depressing synapse. In some preparations, elimination of the synapse had no effect on the period of the rhythm, whereas in other preparations, there was a significant decrease in the period. We propose that the pyloric network can operate in either of the two modes suggested by the model, depending on the maximal conductance of the depressing synapse.

Figure 1

The PD and LP neurons of the pyloric network make reciprocally inhibitory synapses. (A) Schematic diagram of PD and LP neurons and their connectivity. (B) Simultaneous intracellular recordings of LP and PD in normal saline shows alternating activity. (C) Voltage step depolarizations of the LP neuron in tetrodotoxin produces a graded IPSC in the PD neuron. During each voltage pulse, the IPSC depresses; it recovers between pulses. The recovery from depression is a direct function of the time interval between pulses. The LP neuron was voltage clamped with a holding potential of −60 mV. The PD neuron was voltage clamped at a constant potential of −35 mV and the synaptic currents were measured. B and C are recordings from the same experimental preparation.

Figure 2

The LP neuron affects the period of the PD neuron oscillation only in some preparations. (A) The PD neuron activity in two different biological preparations (Biological 1 and 2). In each preparation, the PD neuron activity is shown when the LP neuron was present (Top), continually hyperpolarized (Middle), or briefly hyperpolarized and released from hyperpolarization (Bottom). The thick horizontal bars indicate −10 nA DC current injection in the LP neuron. In both preparations, release of the LP neuron from a brief hyperpolarization resulted in a large IPSP and delay of the next PD neuron burst, indicating the presence of a strong LP–PD synapse. In Biological 1, the period of the PD neuron oscillation was not affected by the continual hyperpolarization of the LP neuron. In Biological 2, the period of oscillation increased by 15% as a result of the continual hyperpolarization of the LP neuron. (B) The same phenomenon is shown in the model of the network. Left traces show the model PD neuron membrane potential when the maximal conductance _syn of the LP–PD synapse was 1.5 mS/cm². Right traces show the same when _syn=2 mS/cm². Time scale indicated by the horizontal bar is 500 msec for Biological 1 and the model traces and 750 msec for Biological 2. (C) Model traces of the LP–PD synaptic conductance g_Syn and the membrane potentials of the PD and LP neurons for B. When _syn was increased from 1.5 to 2 mS/cm², the amplitude of g_Syn increased 6-fold. The amplitude of the PD and LP membrane potentials also increased, and the rhythm slowed. Dotted line denotes −71 mV, the midpoint of the steady-state depression curve h_Syn,∞.

Figure 3

The frequency of the pyloric rhythm may be regulated by a switch mechanism. (A) The model oscillation period plotted against _Syn, when this synapse is not depressing (h_Syn ≡ 1; ▵) and when it is depressing (●). When the synapse is depressing, the rhythm period changes discontinuously at _syn = 1.54 mS/cm² (the switch value) from 780 to 820 msec. (B) Steady-state activation (m_Syn,∞; dashed line) and depression (h_Syn,∞; solid line) curves for the LP–PD synapse plotted as function of V_LP. Shown below the curves are the range of the V_LP values during oscillations in the pacemaker-dominated (open bar) and the synapse-dominated (filled bar) regimes. (C) Schematic diagram shows the cellular and synaptic events that trigger a regenerative loop when _syn is increased beyond the switch value (top arrow).

Figure 4

The switch mechanism can produce bistability in the network oscillations. Same model parameters as in Fig. 3A, but the time constant for recovery from depression of the LP–PD synapse is halved (see Methods). (A) Hysteresis seen in the model oscillation period plotted against maximal conductance (_syn) of the LP–PD synapse. This plot shows the period of oscillation for 84 simulation runs. From run to run, _syn was incrementally increased (from 0 to 2, in steps of 0.05; all units in mS/cm²). For each run, the period after the transient was measured. The end point of each simulation run was used as the initial point in the next run. The shaded area highlights the region of bistability. (B) Bistability shown in the model time traces of the LP–PD synaptic conductance (g_syn) and the membrane potential of the PD neuron for _syn = 0.6 mS/cm² (within the shaded region in A). Also shown is the cycle-to-cycle period of oscillation. From t = 9 to 9.5 sec, a negative current (−0.1 μA/cm²) was injected in the LP neuron. This transient current switched the rhythm from a fast period (800 msec) to a slow period (1,090 msec), and the amplitude of the PD neuron membrane potential excursions also increased. From t = 30 to 34 sec, a positive current (+0.1 μA/cm²) was injected in the LP neuron. This transient current switched the rhythm back to the initial fast oscillation. (C) Synaptic depression curve h_Syn,∞ for the LP–PD synapse as shown in Fig. 3B (solid line) and as a step function (dotted line) centered at V_1/2. Shown below the curves are the range of the V_LP values during oscillations in the pacemaker-dominated (open bar) and the synapse-dominated (filled bar) regimes.

Figure 5

The switch mechanism provides a novel view of synaptic depression. (A) Traditional view of synaptic depression: hyperpolarization of the presynaptic LP neuron results in a transient increase in the strength of the depressed synapse. (B) A novel view of synaptic depression: through a switch mechanism, the interaction between synaptic dynamics and network mechanisms allows a depressed synapse to become lastingly strong.