Biomedical subjects

Jonathan R McDearmid

Publications and source records attributed to Jonathan R McDearmid.

6 recordsLinked to original sources

PubMed2006

Glycine receptors regulate interneuron differentiation during spinal network development.

Glycinergic and GABAergic excitatory chloride-mediated signaling is often the first form of activity to emerge in the nascent nervous system and has been proposed to be essential for several aspects of nervous system development. However, few studies have examined the effects of disrupting glycinergic transmission. Here we perturbed glycinergic transmission in vivo from the onset of development in zebrafish and examined its impact on the formation of the locomotor circuitry. Targeted knockdown of the embryonic glycine receptor alpha2-subunit disrupted rhythm-generating networks and reduced the frequency of spontaneous glycinergic and glutamatergic events. Immunohistochemistry revealed a reduction in the number of spinal interneurons without affecting sensory and motor neurons. This effect was accompanied by a concomitant increase in the number of mitotic cells, suggesting that glycine receptors regulate interneuron differentiation during early development. Despite the loss of many interneurons, a subthreshold rhythm-generating circuit was still capable of forming. These data provide evidence that glycine receptors, in addition to their role in neurotransmission, regulate interneuron differentiation during development of this central neural network.

Animals↗

PubMed2005

Rhythmic motor activity evoked by NMDA in the spinal zebrafish larva.

We have examined the localization and activity of the neural circuitry that generates swimming behavior in developing zebrafish that were spinalized to isolate the spinal cord from descending brain inputs. We found that addition of the excitatory amino acid agonist N-methyl-d-aspartate (NMDA) to spinalized zebrafish at 3 days in development induced repeating episodes of rhythmic tail beating activity reminiscent of slow swimming behavior. The neural correlate of this activity, monitored by extracellular recording comprised repeating episodes of rhythmic, rostrocaudally progressing peripheral nerve discharges that alternated between the two sides of the body. Motoneuron recordings revealed an activity pattern comprising a slow oscillatory and a fast synaptic component that was consistent with fictive swimming behavior. Pharmacological and voltage-clamp analysis implicated glycine and glutamate in generation of motoneuron activity. Contralateral alternation of motor activity was disrupted with strychnine, indicating a role for glycine in coordinating left-right alternation during NMDA-induced locomotion. At embryonic stages, while rhythmic synaptic activity patterns could still be evoked in motoneurons, they were typically lower in frequency. Kinematic recordings revealed that prior to 3 days in development, NMDA was unable to reliably generate rhythmic tail beating behavior. We conclude that NMDA induces episodes of rhythmic motor activity in spinalized developing zebrafish that can be monitored physiologically in paralyzed preparations. Therefore as for other vertebrates, the zebrafish central pattern generator is intrinsic to the spinal cord and can operate in isolation provided a tonic source of excitation is given.

Animals↗

PubMed2003

Steps during the development of the zebrafish locomotor network.

This review summarizes recent data from our lab concerning the development of motor activities in the developing zebrafish. The zebrafish is a leading model for studies of vertebrate development because one can obtain a large number of transparent, externally and rapidly developing embryos with motor behaviors that are easy to assess (e.g. for mutagenic screens). The emergence of embryonic motility was studied behaviorally and at the cellular level. The embryonic behaviors appear sequentially and include an early, transient period of spontaneous, alternating tail coilings, followed by responses to touch, and swimming. Patch clamp recording in vivo revealed that an electrically coupled network of a subset of spinal neurons generates spontaneous tail coiling, whereas a chemical (glutamatergic and glycinergic) synaptic drive underlies touch responses and swimming and requires input from the hindbrain. Swimming becomes sustained in larvae once serotonergic neuromodulatory effects are integrated. We end with a brief overview of the genetic tools available for the study of the molecular determinants implicated in locomotor network development in the zebrafish. Combining genetic, behavioral and cellular experimental approaches will advance our understanding of the general principles of locomotor network assembly and function.

Animals↗

PubMed2003

Mechanisms underlying the noradrenergic modulation of longitudinal coordination during swimming in Xenopus laevis tadpoles.

Noradrenaline (NA) is a potent modulator of locomotion in many vertebrate nervous systems. When Xenopus tadpoles swim, waves of motor neuron activity alternate across the body and propagate along it with a brief rostro-caudal delay (RC-delay) between segments. We have now investigated the mechanisms underlying the reduction of RC-delay s by NA. When recording from motor neurons caudal to the twelfth postotic cleft, the mid-cycle inhibition was weak and sometimes absent, compared to more rostral locations. NA enhanced and even unmasked inhibition in these caudal neurons and enhanced inhibition in rostral neurons, but to a lesser extent. Consequently, the relative increase in the amplitude of the inhibition was greater in caudal neurons, thus reducing the RC-inhibitory gradient. We next investigated whether NA might affect the electrical properties of neurons, such that enhanced inhibition under NA might promote postinhibitory rebound firing. The synaptic inputs during swimming were simulated using a sustained positive current, superimposed upon which were brief negative currents. When these conditions were held constant NA enhanced the probability of rebound firing--indicating a direct effect on membrane properties--in addition to any indirect effect of enhanced inhibition. We propose that NA preferentially enhances weak caudal inhibition, reducing the inhibitory gradient along the cord. This effect on inhibitory synaptic transmission, comprising parallel pre- and postsynaptic components, will preferentially facilitate rebound firing in caudal neurons, advancing their firing relative to more rostral neurons, whilst additionally increasing the networks ability to sustain the longer cycle periods under NA.

Adrenergic alpha-Agonists↗

PubMed2002

Development of the locomotor network in zebrafish.

The zebrafish is a leading model for studies of vertebrate development and genetics. Its embryonic motor behaviors are easy to assess (e.g. for mutagenic screens), the embryos develop rapidly (hatching as larvae at 2 days) and are transparent, permitting calcium imaging and patch clamp recording in vivo. We review primarily the recent advances in understanding the cellular basis for the development of motor activities in the developing zebrafish. The motor activities are generated largely in the spinal cord and hindbrain. In the embryo these segmented structures possess a relatively small number of repeating sets of identifiable neurons. Many types of neurons as well as the two types of muscle cells have been classified based on their morphologies. Some of the molecular signals for cellular differentiation have been identified recently and mutations affecting cell development have been isolated. Embryonic motor behaviors appear in sequence and consist of an early period of transient spontaneous coiling contractions, followed by the emergence of twitching responses to touch, and later by the ability to swim. Coiling contractions are generated by an electrically coupled network of a subset of spinal neurons whereas a chemical (glutamatergic and glycinergic) synaptic drive underlies touch responses and swimming. Swimming becomes sustained in larvae once the neuromodulatory serotonergic system develops. These results indicate many similarities between developing zebrafish and other vertebrates in the properties of the synaptic drive underlying locomotion. Therefore, the zebrafish is a useful preparation for gaining new insights into the development of the neural control of vertebrate locomotion. As the types of neurons, transmitters, receptors and channels used in the locomotor network are being defined, this opens the possibility of combining cellular neurophysiology with forward and reverse molecular genetics to understand the principles of locomotor network assembly and function.

Animals↗

PubMed2002

AMRP peptides modulate a novel K(+) current in pleural sensory neurons of Aplysia.

Modulation of Aplysia mechanosensory neurons is thought to underlie plasticity of defensive behaviors that are mediated by these neurons. In the past, identification of modulators that act on the sensory neurons and characterization of their actions has been instrumental in providing insight into the functional role of the sensory neurons in the defensive behaviors. Motivated by this precedent and a recent report of the presence of Aplysia Mytilus inhibitory peptide-related (AMRP) neuropeptides in the neuropile and neurons of the pleural ganglia, we sought to determine whether and how pleural sensory neurons respond to the AMRPs. In cultured pleural sensory neurons under voltage clamp, AMRPs elicited a relatively rapidly developing, then partially desensitizing, outward current. The current exhibited outward rectification; in normal 10 mM K(+), it was outward at membrane potentials more positive than -80 mV but disappeared without reversing at more negative potentials. When external K(+) was elevated to 100 mM, the AMRP-elicited current reversed around -25 mV; the shift in reversal potential was as expected for a current carried primarily by K(+). In the high-K(+) solution, the reversed current began to decrease at potentials more negative than -60 mV, creating a region of negative slope resistance in the I-V relationship. The AMRP-elicited K(+) current was blocked by extremely low concentrations of 4-aminopyridine (4-AP; IC(50) = 1.7 x 10(-7) M) but was not very sensitive to TEA. In cell-attached patches, AMRPs applied outside the patch-thus presumably through a diffusible messenger-increased the activity of a K(+) channel that very likely underlies the macroscopic current. The single-channel current exhibited outward rectification, and the open probability of the channel decreased with hyperpolarization; together, these two factors accounted for the outward rectification of the macroscopic current. Submicromolar 4-AP included in the patch pipette blocked the channel by reducing its open probability without altering the single-channel current. Based on the characteristics of the AMRP-modulated K(+) current, we conclude that it is a novel current that has not been previously described in Aplysia mechanosensory neurons. In addition to this current, two other AMRP-elicited currents, a slow, 4-AP-resistant outward current and a Na(+)-dependent inward current, were occasionally observed in the cultured sensory neurons. Responses consistent with all three currents were observed in sensory neurons in situ in intact pleural ganglia.

4-Aminopyridine↗