NEURAL DEVELOPMENT IN THE ABSENCE OF NOREPINEPHRINE

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Alterations in adrenergic transmission occur in anxiety and depressive disorders, and in Alzheimer's disease. In addition, 6 human patients with autonomic failure have been found to be congenitally deficient in the enzyme dopamine (beta-hydroxylase (DBH). They are unable to synthesize the adrenal hormone epinephrine (E) and the adrenergic neurotransmitter norepinephrine (NE). Despite the absence of these transmitters in their brains, these patients have normal mood and mental function. This is surprising given the postulated roles for NE in learning and memory, arousal and attention, and fear and anxiety. Dopamine (DA), the precursor of NE, is stored in and released from the adrenergic terminals of these patients. A hypothesis that could account for normal CNS function in these patients is that their brains develop to utilized DA as the adrenergic transmitter, either by activating dopaminergic or adrenergic receptors. We propose to examine the mouse model (dbh-/-) of human DBH-deficiency to investigate mechanisms that may arise during postnatal development to compensate for the absence of NE. We will determine the number and location of adrenergic cell bodies and terminals in dbh-/- and control mice by several histochemical techniques. We will test for elevated DA receptor expression due to the release of DA in novel locations during development. Because NE is absent, we will also quantitate adrenergic receptor expression. We will characterize the formation of the cerebellum, which has been implicated as being dependent on NE for their proper development. Importantly, any changes we observe in the dbh-/- mice may be due to either the absence of NE or the presence of DA in the adrenergic vesicles. We will create a new mouse model (th-/- /dat-th+/-) to distinguish these etiologies, and to identify any developmental changes due to the loss of NE that are masked by the presence of DA in the dbh-/- mice. Finally we will determine the permanence of phenotypes due to the absence of NE by restoring NE in the mutant mice using amino acid precursors. Results from these studies will determine what are the critical roles of adrenergic signaling in vivo during postnatal neural development, and whether DA can substitute for NE in the CNS.