Metaplastic Facilitation and Ultrastructural Changes in Synaptic Properties Are Associated with Long-Term Modulation of the Lamprey Locomotor Network

Abstract

The neuropeptide substance P evokes a long-term protein synthesis-dependent increase in the cycle frequency of locomotor network activity in the lamprey. Although cellular and synaptic mechanisms that could induce this effect have been identified, nothing is known of the underlying maintenance mechanisms. These mechanisms have been examined here.Substance P potentiates low-frequency-evoked EPSPs from excitatory network interneurons. It also converts the depression of the EPSP during spike trains into facilitation, an example of metaplasticity. The metaplasticity was associated with a reduction of the transmitter release probability but an increase in the number of release sites. Although the potentiation of low-frequency-evoked EPSPs recovered within 1 hr, the metaplastic facilitation had not recovered 3-4 hr after substance P application. The metaplasticity thus extended into the protein synthesis-dependent maintenance phase of the network modulation, making it the only identified cellular or synaptic effect of substance P to last this long. It also had the same induction and maintenance features as the network burst frequency modulation, further suggesting that the two effects were related.Long-term changes in synaptic properties are often associated with changes in synaptic organization. We have thus also examined the effects of substance P on synaptic ultrastructure up to 5 hr after substance P application. Substance P had several significant effects. These included an increase in the number of docked vesicles and a reduction of the synaptic gap.Substance P thus has long-term effects on synaptic organization and function. The relevance of these effects to the long-term locomotor network modulation is discussed.

Modulation of Cellular and Synaptic Variability in the Lamprey Spinal Cord

“…A reduction in q or n will thus reduce the synaptic variance, but there is a parabolic relationship between the synaptic variance and p (Clements and Silver 2000). Substance P reduces p, increases the number of release sites and docked vesicles, and increases the quantal amplitude (Bevan and Parker 2004), effects that are not consistent with a reduction in the variability of the quantal content.…”

“…Note that in addition to reduced variability, substance P increased number of vesicles (Bevan and Parker 2004 the intrinsic properties of motor neurons but to a reduction in variability of the excitatory drive that the motor neurons received. This could be caused by the reduced variability of EIN spiking or by the reduced variance of EIN-and EScINevoked EPSPs.…”

“…Insight into the mechanisms underlying changes in cellular and synaptic properties can help to link these effects to changes in the network output (Bevan and Parker 2004). The mechanisms underlying the reduced variance of EIN-evoked EPSPs were thus examined.…”

“…We have tried to link cellular, synaptic, and network effects of substance P by correlating effects at different levels. Over a series of studies, we have linked metaplastic changes in EIN-evoked EPSPs to substance P-evoked changes in the network burst frequency (Bevan and Parker 2004;Parker and Grillner 1999;. Because the effect on the network burst regularity has not been studied previously at the cellular and synaptic levels, the description of variability in this study is an essential initial step in this analysis.…”

What Is Being Trained? How Divergent Forms of Plasticity Compete To Shape Locomotor Recovery after Spinal Cord Injury

“…[124][125][126][127] Several groups have subsequently demonstrated the existence of metaplasticity in spinal cord locomotor circuitry below SCI. [128][129][130][131][132] Understanding spinal cord (re)-training potential as a form of metaplasticity provides a fertile literature to draw from for pharmacological targets to carefully tune and improve spinal cord training after injury.…”