Hypercapnic ventilatory response in mice lacking the 65 kDa isoform of Glutamic Acid Decarboxylase (GAD65)

BackgroundRecent reports have shown that there are developmental changes in theventilatory response to hypercapnia in the rat. These are characterizedby an initial large response to carbon dioxide immediately after birthfollowed by a decline with a trough at one week of age, followed by areturn in sensitivity. A second abnormality is seen at postnatal day 5(P5) rats in that they cannot maintain the increase in frequency for 5min of hypercapnia. In mice lacking GAD65 the release of GABA duringsustained synaptic activation is reduced. We hypothesized that thisdevelopmental pattern would be present in the mouse which is also lessmature at birth and that GABA mediates this relative respiratorydepression.MethodsIn awake C57BL/6J and GAD65-/- mice the ventilatory response to 5%carbon dioxide (CO2) was examined at P2, P4, P6, P7, P12.5, P14.5 andP21.5, using body plethysmography.ResultsMinute ventilation (VE) relative to baseline during hypercapnia from P2through P7 was generally less than from P12.5 onwards, but there was notrough as in the rat. Breaking VE down into its two components showedthat tidal volume remained elevated for the 5 min of exposure to 5% CO2.At P6, but not at other ages, respiratory frequency declined with timeand at 5 min was less that at 2 and 3 min. GAD65-/- animals at P6 showeda sustained increase in respiratory rate for the five mins exposure toCO2.ConclusionThese results show, that in contrast to the rat, mice do not show adecline in minute ventilatory response to CO2 at one week of age.Similiar to the rat at P5, mice at P6 are unable to sustain an increasein CO2 induced respiratory frequency and GAD65 contributes to this falloff.