DNA methyltransferase I (Dnmt1), the maintenance enzyme for DNA cytosine methylation, is expressed at high levels in the CNS during embryogenesis and after birth. Because embryos deficient for Dnmt1 die at gastrulation, the role of Dnmt1 in the development and function of the nervous system could not be studied by using this mutation. We therefore used the cre/loxP system to produce conditional mutants that lack Dnmt1 in neuroblasts of embryonic day 12 embryos or in postmitotic neurons of the postnatal animal. Conditional deletion of the Dnmt1 gene resulted in rapid depletion of Dnmt1 proteins, indicating that the enzyme in postmitotic neurons turns over quickly. Dnmt1 deficiency in postmitotic neurons neither affected levels of global DNA methylation nor influenced cell survival during postnatal life. In contrast, Dnmt1 deficiency in mitotic CNS precursor cells resulted in DNA hypomethylation in daughter cells. Whereas mutant embryos carrying 95% hypomethylated cells in the brain died immediately after birth because of respiratory distress, mosaic animals with 30% hypomethylated CNS cells were viable into adulthood. However, these mutant cells were eliminated quickly from the brain within 3 weeks of postnatal life. Thus, hypomethylated CNS neurons were impaired functionally and were selected against at postnatal stages.

Many processes in mammalian and invertebrate central nervous systems exhibit habituation and/or sensitization of their responses to repetitive stimuli. Here, we studied the adaptive behaviours of the respiratory pattern generator in rat on repetitive vagal‐afferent stimulation and compared these behaviours obtained in vivo with the reported effects of such stimuli on synaptic transmission in the corresponding signal pathway in vitro. Sustained (1 min) electrical pulsed stimulation of the vagus nerve elicited the classic Hering‐Breuer (HB) reflex slowing of the respiratory rhythm followed by a bi‐exponential recovery, and a post‐stimulus rebound (PR). The recovery from the HB reflex satisfied the classic criteria of habituation. The fast component of the recovery and the PR were abolished by systemic administration of an NMDA receptor antagonist or electrolytic lesioning of the pontine Kölliker‐Fuse nucleus. The characteristics of the fast recovery and PR suggest a vagally induced desensitization of the NMDA receptor‐dependent pontine input to the respiratory pattern generator. The slow component of recovery persisted after both experimental interventions and accounted for the habituation to the vagal input. The characteristics of the slow recovery in vivo were reminiscent of the reported synaptic accommodation in vitro in the medullary region where vagal afferents terminate. The habituation of vagal input and desensitization of pontine input act in concert to offset the HB reflex. Such simultaneous habituation‐desensitization in parallel neural pathways with differing sensitivities to NMDA receptor activation represent a hitherto unknown pairing of dual non‐associative learning processes in the mammalian brain.

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