Long-Term Plasticity of the Spinal Locomotor Circuitry Mediated by Endocannabinoid and Nitric Oxide Signaling

Abstract

Retrograde signaling by endocannabinoids is known to induce short-and long-term synaptic plasticity, but the significance of this modulation for the activity of neural networks underlying motor behavior is largely unclear. Here, we used the isolated lamprey spinal cord to show that endocannabinoids released by activation of metabotropic glutamate receptor 1 (mGluR1) induce long-term synaptic plasticity during an ongoing locomotor rhythm and how this is translated onto the integrated activity of the spinal circuitry. A brief activation of mGluR1 induces a long-term increase in the locomotor frequency that is mediated by a concomitant long-term depression of midcycle reciprocal inhibition and long-term potentiation of ipsilateral synaptic excitation arising from locomotor circuit interneurons. Blockade of cannabinoid receptors with AM251 prevented the mGluR1-mediated long-term plasticity of both inhibitory and excitatory synaptic transmission, as well as that of the locomotor activity. Similarly, inhibition of nitric oxide signaling blocked the mGluR1-mediated long-term plasticity. These results show that the locomotor circuitry is endowed with a "memory" capacity mediated by a long-term shift in the balance between synaptic inhibition and excitation. This is triggered by activation of mGluR1 and requires subsequent endocannabinoid and nitric oxide signaling.

Nitric Oxide Potentiation of Locomotor Activity in the Spinal Cord of the Lamprey

“…In addition to its direct effect on synaptic transmission, NO seems to act in a synergistic manner together with endocannabinoids to mediate the long-term potentiation of the locomotor frequency induced by activation of mGluR1 (Kyriakatos and El Manira, 2007). Although a long-lasting effect of NO donors on the locomotor frequency was seen in some preparations, this was not always the case.…”

“…The synaptic activation of neurons can trigger an influx of calcium (e.g., through NMDA channels) and the resulting NOS activation produces NO that can influence neighboring cells, including presynaptic terminals, thereby providing a link between presynaptic and postsynaptic activity. In addition, NO signaling can interact with endocannabinoids to modify transmitter release (Kyriakatos and El Manira, 2007;Makara et al, 2007). However, the sources and mechanisms of NO action in the nervous system are not completely understood.…”

“…The aim of this study, therefore, was to examine the origin, effects and mechanisms of action of NO in the swimming system of the lamprey. The present study was partly prompted by the recent demonstration that NO is involved in the potentiation of the locomotor frequency following mGluR1 receptor activation (Kyriakatos and El Manira, 2007).…”

The Nitric Oxide/cGMP Pathway Tunes the Thermosensitivity of Swimming Motor Patterns inXenopus laevisTadpoles

“…The modulatory effects of NO on a variety of neuronal circuits across different phyla have been described. NO affects rhythmic motor activity in jellyfish swimming (Moroz et al, 2004), snail feeding (Kobayashi et al, 2000), and cardiac activity (Taylor et al, 2003), crab stomatogastric activity (Scholz et al, 2001;Stein et al, 2005), locust oviposition (Newland and Yates, 2007), and mouthpart movements (Rast, 2001), frog respiration (Hedrick and Morales, 1999), tadpole swimming (McLean and Sillar, 2000), lamprey swimming (Kyriakatos and El Manira, 2007), and mammalian respiration (Pierrefiche et al, 2007;Reeves et al, 2008). The mechanisms NO uses to exert its effects are less well known, with a notable exception being in the tadpole spinal cord Sillar, 2002, 2004).…”

“…These are modifications that would conserve energy. Moreover, the modulation of spinal circuitry by NO is long lasting (Kyriakatos and El Manira, 2007), befitting a response to a changing environment.…”