Neonatal maturation of the hypercapnic ventilatory response and central neural CO2 chemosensitivity

Abstract

The ventilatory response to CO2 changes as a function of neonatal development. In rats, a ventilatory response to CO2 is present in the first 5 days of life, but this ventilatory response to CO2 wanes and reaches its lowest point around postnatal day 8. Subsequently, the ventilatory response to CO2 rises towards adult levels. Similar patterns in the ventilatory response to CO2 are seen in some other species, although some animals do not exhibit all of these phases. Different developmental patterns of the ventilatory response to CO2 may be related to the state of development of the animal at birth. The triphasic pattern of responsiveness (early decline, a nadir, and subsequent achievement of adult levels of responsiveness) may arise from the development of several processes, including central neural mechanisms, gas exchange, the neuromuscular junction, respiratory muscles and respiratory mechanics. We only discuss central neural mechanisms here, including altered CO2 sensitivity of neurons among the various sites of central CO2 chemosensitivity, changes in astrocytic function during development, the maturation of electrical and chemical synaptic mechanisms (both inhibitory and excitatory mechanisms) or changes in the integration of chemosensory information originating from peripheral and multiple central CO2 chemosensory sites. Among these central processes, the maturation of synaptic mechanisms seems most important and the relative maturation of synaptic processes may also determine how plastic the response to CO2 is at any particular age.

Fig. 1

The early development of the ventilatory response to inspired hypercapnia. A plot of the % increase in ventilation (comparing ventilation while inspiring 5% CO₂ vs. inspiring room air) as a function of the day after birth in neonatal rats. Three phases are evident in the early development: (I) an early ventilatory response to inspired hypercapnia that wanes during the first week of life; (II) a critical window of minimal ventilatory response to inspired hypercapnia; (III) an increase in the ventilatory response to inspired hypercapnia to levels comparable to adults during the second week of life. This figure was drawn based on the data from Stunden et al. (2001); the detailed elements of the pattern may vary in different species.

Fig. 2

The effect of various protocols for exposure to chronic hypercapnia (CHC) on the development of the ventilatory response to inspired hypercapnia in neonatal rats. The three phases, as described in Fig. 1 are shown with different shading: phase I, gray; phase II, white; phase III, black. The normal pattern of development (CON) is shown below the time line. When exposure to chronic hypercapnia is initiated 5 days before birth and continued until the ventilatory response is tested (CHC-1), the three phases appear but the transition between the phases is right-shifted, i.e. they occur later in development. In contrast, when exposure to chronic hypercapnia is initiated after the rats are born and continued for 7 days (CHC-2), phase III does not occur (up to day P20).

Fig. 3

The major factors contributing to developmental changes in the ventilatory response to CO₂ are shown above. In the early postnatal period, GABA may cease to be an excitatory (‘exc.’) neurotransmitter, and excitatory inputs from gap junctions may decline over the entire period of development. Both of these changes may contribute to the early decline in CO₂ responsiveness. The role of peripheral CO₂ chemoreceptors and the neuronal sensitivity to CO₂ among central chemosensory sites seems stable over the course of development. Synaptogenesis and the emergence of excitatory neurotransmitters probably participate in the emergence of adult levels of ventilatory responsiveness to CO₂. Astrocytes proliferate and mature after ~P8, and they may increase neuronal activity in CO₂ chemosensory areas although this hypothesis has not been firmly established.