Neuromodulators, such as Substance P (SubP) play an important role in modulating many rhythmic activities driven by central pattern generators (e.g., locomotion, respiration). However, the mechanism by which SubP enhances breathing regularity has not been determined. Here, we used mouse brainstem slices containing the pre-Bötzinger Complex (Pre-BötC) to demonstrate, for the first time, that SubP activates transient receptor protein canonical (TRPC) channels to enhance respiratory rhythm regularity. Moreover, SubP enhancement of network regularity is accomplished via selective enhancement of ICAN-dependent intrinsic bursting properties. In contrast to INaPdependant pacemakers, ICAN-dependant pacemaker bursting activity is TRPC dependent. Western Blots reveal TRPC3 and TRPC7 channels are expressed in rhythmically active ventral respiratory group (VRG) island preparations. Taken together, these data suggest that SubPmediated activation of TRPC3/7 channels underlies rhythmic ICAN-dependent pacemaker activity and enhances the regularity of respiratory rhythm activity.

Motor behaviors of some species, such as the rat and the human baby, are quite immature at birth. Here we review recent data on some of the mechanisms underlying the postnatal maturation of posture in the rat, in particular the development of pathways descending from the brain stem and projecting onto the lumbar enlargement of the spinal cord. A short-lasting depletion in serotonin affects both posture and the excitability of motoneurons. Here we try to extrapolate to human development and suggest that the abnormalities in motor control observed in childhood—e.g, deficits in motor coordination—might have their roots in the prenatal period, in particular serotonin depletion due to exposure to several environmental and toxicological factors during pregnancy.

Visual Abstract

Rhythm generating neural circuits underlying diverse behaviors such as locomotion, sleep states, digestion and respiration play critical roles in our lives. Irregularities in these rhythmic behaviors characterize disease states -thus, it is essential that we identify ionic and/or cellular mechanisms that are necessary for triggering these rhythmic behaviors on a regular basis. Here, we examine which ionic conductances underlie regular or "stable" respiratory activities, proposed to underlie eupnea, or normal quiet breathing. We used a mouse in vitro medullary slice preparation containing the rhythmogenic respiratory neural circuit, called the preBötzinger Complex (preBötC) that underlies inspiratory respiratory activity. We varied either [K + ] o , [Na + ] o , or blocked voltage gated calcium channels (VGCC) while recording from synaptically isolated respiratory pacemakers and examined which of these manipulations resulted in their endogenous bursting to become more irregular. Of these, lowering [Na + ] o increased the irregularity of endogenous bursting by synaptically isolated pacemakers. Lowering [Na + ] o also decreased the regularity of fictive eupneic activity generated by the ventral respiratory group (VRG) population and hypoglossal motor output. Voltage clamp data indicate that lowering [Na + ] o , in a range that results in irregular population rhythm generation, decreased persistent sodium currents, but not transient sodium currents underlying action potentials. Our data suggest that background sodium currents play a major role in determining the regularity of the fictive eupneic respiratory rhythm.

Metabotropic glutamate receptors (mGluR) are hypothesized to play a key role in generating the central respiratory rhythm and other rhythmic activities driven by central pattern generators (e.g., locomotion). Yet, the functional role of mGluR in rhythmic respiratory activity and many motor patterns is very poorly understood. Here, we used mouse respiratory brain-slice preparations containing the pre-Bötzinger Complex (pre-BötC) to identify the role of group I mGluR (mGluR1 and mGluR5) in respiratory rhythm generation. We found that activation of mGluR1/5 is not required for the pre-BötC to generate a respiratory rhythm. However, our data suggest that mGluR1 and mGluR5 differentially modulate the respiratory rhythm. Blocking endogenous mGluR5 activity with MPEP decreases the inspiratory burst duration, burst area and frequency, while it increases the irregularity of the fictive eupneic inspiratory rhythm generated by the pre-BötC. In contrast, blocking mGluR1 reduces the frequency. Moreover, the mGLUR1/5 agonist DHPG increases the frequency and decreases the irregularity of the respiratory rhythm. Based on prior studies, we hypothesized that mGluR-signaling decreases the irregularity of the respiratory rhythm by activating transient receptor potential canonical (TRPC) channels, that carry a non-specific cation current (ICAN). Indeed, DHPG application reduces cycle-by-cycle variability and subsequent application of the TRPC channel blocker SKF-96365 reverses this effect. Our data suggest that mGluR5 activation of ICAN-carrying TRPC channels plays an important role in governing the cycle-by-cycle variability of the respiratory rhythm. These data suggest that modulation of TRPC channels may correct irregular respiratory rhythms in some central neuronal diseases.