Cellular and Synaptic Modulation Underlying Substance P-Mediated Plasticity of the Lamprey Locomotor Network

Abstract

The tachykinin substance P modulates the lamprey locomotor network by increasing the frequency of NMDA-evoked ventral root bursts and by making the burst activity more regular. These effects can last in excess of 24 hr. In this paper, the effects of substance P on the synaptic and cellular properties of motor neurons and identified network interneurons have been examined. Substance P potentiated the amplitude of monosynaptic glutamatergic inputs from excitatory interneurons and reticulospinal axons. The amplitude and frequency of miniature EPSPs was increased, suggesting that the synaptic modulation was mediated presynaptically and postsynaptically. The postsynaptic modulation was caused by a specific effect of substance P on the NMDA component of the synaptic input, whereas the presynaptic component was calcium-independent. Substance P did not affect monosynaptic glycinergic inputs from lateral interneurons, crossed inhibitory interneurons, or ipsilateral segmental interneurons or postsynaptic GABAA or GABAB responses, suggesting that it has little effect on inhibitory synaptic transmission. At the cellular level, substance P increased synaptic inputs, resulting in membrane potential oscillations in motor neurons, crossed caudal interneurons, lateral interneurons, and excitatory interneurons. The spiking in response to depolarizing current pulses was increased in motor neurons, lateral interneurons, and excitatory interneurons, but usually was reduced in crossed inhibitory interneurons. Substance P reduced the calcium-dependent afterhyperpolarization after an action potential in motor neurons and lateral interneurons, but did not affect this conductance in excitatory or crossed inhibitory interneurons. The relevance of these cellular and synaptic changes to the modulation of the locomotor network is discussed.

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“…These EPSPs evoked from retinal afferents can be regarded as monosynaptic (n = 4; Fig. 2H, lower traces), because they have a fixed latency and persist during perfusion with high concentrations of calcium (4 mM) and magnesium (8 mM), which significantly reduces the probability of polysynaptic effects (48)(49)(50). Furthermore, to show that the retinal afferents form close appositions on the dendrites of the output cells (Fig.…”

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“…Understanding such interactions is particularly challenging in mammals because of the great complexity of their CNS and simpler models are needed. The CNS of lampreys provides excellent accessibility to cell networks as well as the possibility to identify detailed cellular mechanisms underlying behaviors (McClellan and Grillner, 1984;Di Prisco et al, 1997Parker and Grillner, 1998;Grillner et al, 2001). In the spinal cord, synaptic inputs were shown to be essential to generate the basic locomotor pattern (Buchanan, 1999(Buchanan, , 2001, and yet, postinhibitory rebound and bistable membrane properties contribute significantly (Wallén and Grillner, 1987;Matsushima et al, 1993;el Manira et al, 1994;Tegnér et al, 1997).…”

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“…They act almost exclusively through G protein-coupled receptors [88]. tachykinin receptors [94]). Unlike peptide antagonists, nonpeptide antagonists are metabolically stable, orally active, and can cross the blood-brain barrier.…”

“…Second generation compounds (e.g. the CCK B receptor antagonists L368935 and L740093, and the NK 1 tachykinin receptor antagonist CP99994 [94]) have enhanced solubility and specificity. For example, CCK B antagonists were based on a series of benzodiazepine derivatives containing a cationic solubilizing group for improved solubility and up to 100 times greater affinity.…”

“…Allosteric modulators have also been identified for β-adrenoceptors, adenosine receptors, and serotonin receptors. Non-peptide antagonists of neuropeptide receptors may act through these allosteric binding sites [94]. These sites provide potential targets for therapeutic interventions, as drugs that target these sites may have more subtle effects on function than agonists or antagonists that either block or activate the receptor.…”