Role of fast inhibitory synaptic mechanisms in respiratory rhythm generation in the maturing mouse.

Abstract

1. The importance of glycinergic and GABAAergic synaptic mechanisms for respiratory rhythm generation in the maturing mouse were investigated in vivo and in an in vitro slice preparation generating respiratory rhythmic activity spontaneously at all postnatal ages. 2. The effect on respiration of topical application of strychnine or bicuculline to the surface of the ventrolateral medulla was assessed in spontaneously breathing anaesthetized mice of different ages (postnatal (P) days 0 to >56). Glycine receptor antagonization with concentrations of strychnine up to 25 uM was ineffective in altering the breathing pattern in neonates (P1-PS) . However, in mature mice (P > 15), low doses of strychnine (0f2-2 uM) abolished regular rhythmic discharge in the phrenic nerve. Bicuculline (0 5-50 /M) produced dose-dependent increases in inspiratory time, amplitude and cycle length of phrenic nerve discharge in anaesthetized neonatal mice whereas both cycle length and duration of inspiratory activity were reduced in mature animals. In addition, in both neonates and mature mice low concentrations of bicuculline (0 5-5 /M) abolished phrenic nerve discharge intermittently. 3. The response of respiratory-modulated hypoglossal (XII) neurones recorded in tilted sagittal slices from newborn and mature mice during blockade of glycine and GABAA receptors was similar to the phrenic nerve changes observed in vivo: in slices from neonates, the rhythmic activity of XII neurones was resistant to concentrations of strychnine up to 50/uM whereas low doses of strychnine (02-2 /M) abolished rhythmic activity in preparations from mature mice. Bicuculline (1-50 /M) produced a dosedependent prolongation of burst duration and a slowing of rhythmic discharge in slices from neonatal mice whereas in mature mice rhythmic XII bursts were shortened and their frequency increased. At all maturational stages, bicuculline (1-50,UM) induced severe disruption of the regular rhythm of XII neurone activity causing maintained depolarizations and oscillations in membrane potential. 4. On-going inhibitory postsynaptic potentials of neurones located in the ventral respiratory group region of tilted sagittal slices from both immature and mature mice were sensitive to low concentrations of either bicuculline or strychnine (1-5 /M) indicating an absence of a maturational change in the sensitivity of GABAA and glycine receptors to their respective antagonists.5. We conclude that over the first 15 days of life in the mouse there is a dramatic increase in the relevance of glycine receptors for respiratory rhythm generation, and change in the functional role of GABAA receptors within the respiratory network, which may provide a stabilizing influence on neurones within the respiratory network from birth onwards.The underlying neural mechanisms for respiratory synaptic mechanisms within the mammalian nervous rhythm generation may be quite different in newborn and system during the first weeks of life. An increase in adult mammals. Indeed, there is a wealth of information p...

Reconfiguration of respiratory-related population activity in a rostrally tilted transversal slice preparation following blockade of inhibitory neurotransmission in neonatal rats

“…Neverthe-less, specific compartments, which particularly include the pre-BötC, maintain their rhythmic activity in vitro [26], and such rhythmic slice preparations were extensively used to study cellular mechanisms of the primary respiratory-like rhythm generation. Previous studies showed that synaptic inhibition is functional in slices, but its contribution to the generation of the neonatal respiratory-related rhythm was considered to be marginal [21,48,49]. In that regard, our data are in full accordance with these previous studies because the in vitro rhythm never stopped after blockade of inhibitory neurotransmission.…”

“…One hypothesis suggests that in particular synaptic inhibition becomes more important for respiratory rhythm generation during ontogeny [9,10,20,21]. Nevertheless, synaptic inhibition is required from birth on to generate a physiological threephase motor pattern [22].…”

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

“…The blockage of chloride-dependent inhibition with GlyR antagonists effectively stops regular respiratory rhythmogenesis in adult animals but not in neonates (31). In contrast, the blockage of non-NMDAR in the neonate abolishes respiratory rhythm (14), while the blockage of non-NMDAR and NMDAR is required for the same effect in the adult (11).…”

Blockade of synaptic inhibition within the pre‐Bötzinger complex in the cat suppresses respiratory rhythm generation in vivo

“…Synaptic inhibition results in reversible and irreversible switching off of phasic activities and shaping of neuronal discharge patterns (Richter, Camerer, Meesmann & R ohrig, 1979;Richter, 1982;Ballantyne & Richter, 1986; Remmers, Richter, Ballantyne, Bainton & Klein, 1986; Anders, Ballantyne, Bischoff, Lalley & Richter, 1991;Haji, Takeda & Remmers, 1992;Klages, Bellingham & Richter, 1993;Schmid et al 1996). Blockade of GABAergic and glycinergic mechanisms by systemic or local administration of receptor antagonists greatly disturbs rhythmic respiratory functions when studied under in vivo conditions (Hayashi & Lipsky, 1992) or under in vitro conditions in slice preparations that contain more rostral medullary and pontine structures (Paton, Ramirez & Richter, 1994;Paton & Richter, 1995). These findings, however, are not consistent with reports on experiments performed in en bloc brainstem-spinal cord (Feldman & Smith, 1989;Onimaru, Arata & Homma, 1990) or medullary slice preparations lacking the pons (Ramirez, Quellmalz & Richter, 1996) showing that synaptic inhibition is not essential for the generation and maintenance of the respiratory activity.…”