Article

Sodium and calcium current-mediated pacemaker neurons and respiratory rhythm generation. J Neurosci

Department of Applied Science, College of William and Mary, Williamsburg, Virginia, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 02/2005; 25(2):446-53. DOI: 10.1523/JNEUROSCI.2237-04.2005
Source: PubMed

ABSTRACT The breathing motor pattern in mammals originates in brainstem networks. Whether pacemaker neurons play an obligatory role remains a key unanswered question. We performed whole-cell recordings in the preBotzinger Complex in slice preparations from neonatal rodents and tested for pacemaker activity. We observed persistent Na+ current (I(NaP))-mediated bursting in approximately 5% of inspiratory neurons in postnatal day 0 (P0)-P5 and in P8-P10 slices. I(NaP)-mediated bursting was voltage dependent and blocked by 20 mum riluzole (RIL). We found Ca2+ current (I(Ca))-dependent bursting in 7.5% of inspiratory neurons in P8-P10 slices, but in P0-P5 slices these cells were exceedingly rare (0.6%). This bursting was voltage independent and blocked by 100 microm Cd2+ or flufenamic acid (FFA) (10-200 microm), which suggests that a Ca2+-activated inward cationic current (I(CAN)) underlies burst generation. These data substantiate our observation that P0-P5 slices exposed to RIL contain few (if any) pacemaker neurons, yet maintain respiratory rhythm. We also show that 20 nm TTX or coapplication of 20 microm RIL + FFA (100-200 microm) stops the respiratory rhythm, but that adding 2 mum substance P restarts it. We conclude that I(NaP) and I(CAN) enhance neuronal excitability and promote rhythmogenesis, even if their magnitude is insufficient to support bursting-pacemaker activity in individual neurons. When I(NaP) and I(CAN) are removed pharmacologically, the rhythm can be maintained by boosting neural excitability, which is inconsistent with a pacemaker-essential mechanism of respiratory rhythmogenesis by the preBotzinger complex.

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Available from: Consuelo Morgado-Valle, Apr 13, 2015
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    • "The inspiratory phase of the respiratory cycle in vitro results from preBötC neurons firing a synchronous burst of action potentials (APs) on top of a 10-to 20-mV, 0.3-to 0.8-s depolarization dubbed inspiratory drive potential, which results mainly from AMPA receptor (AMPAR)-mediated postsynaptic currents (Funk et al. 1993; Greer et al. 1991; Morgado-Valle and Feldman 2007). Although preBötC neurons express pacemaking-promoting currents such as persistent Na ϩ current (I NaP ) and Ca 2ϩ -activated nonselective cation current (I CAN ) (Del Negro et al. 2002; Pena and Ramirez 2004), Ͻ10% are intrinsic pacemaker neurons (Del Negro et al. 2005) and the vast majority are nonpacemaker neurons requiring excitatory synaptic input to burst rhythmically. The existence of multiple oscillatory regimes and the state dependence of pacemaker neurons in the preBötC suggest that further studies are needed to understand their role in respiratory rhythm generation (Rybak et al. 2014). "
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    • "Respiratory neurons with intrinsic bursting properties were identified and incorporated into mechanistic computational models for respiratory rhythm generation in neonatal rodents. Experimental evidence suggested that intrinsically bursting respiratory neurons were not necessary for rhythm generation (Del Negro et al., 2005). Since experimental methods do not currently exist for specifically inactivating the specific ionic currents underlying intrinsic bursting properties in respiratory neurons, attention was redirected toward alternative mechanisms underlying rhythmogenesis. "
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