Differential modulation of the cholinergic phenotype of the nucleus basalis magnocellularis neurons by applying NGF at the cell body or cortical terminal fields

Although it is well known that exogenous nerve growth factor (NGF) can dramatically affect the phenotype of the basal forebrain cholinergic neurons in normal, aged, or lesioned animals, whether its actions are restricted to the terminal field level of these cholinergic neurons has yet to be established. In most cases, NGF has been applied into the cerebroventricle space giving it access to both the terminal fields and somatodendritic regions. The recent demonstration that TrkA, the essential component of high-affinity NGF receptors, is expressed not only at the distal fields (terminals and distal axons) but also at the proximal fields (cell bodies, dendrites, and proximal axons) of the basal forebrain cholinergic neurons has provoked renewed interest in this problem, More recently it was further demonstrated that in Alzheimer's disease (AD), the NGF peptide increased throughout the brain but decreased in the nucleus basalis magnocellularis (MBM), suggesting that there is an impaired retrograde transport of NGF from the cortex to the NBM. Thus, it will be crucial to clarify whether or not the TrkA receptors on the somatodendritic fields of the NBM cholinergic neurons respond to exogenous NGF in order to support the rationale for site-directed neurotrophic factor therapy in AD or other neurological disorders. To clarify this issue, we delivered 2.5S purified mouse NGF locally into the cortex or corpus striatum adjacent to the NBM of naive and cortically devascularized mature male Wistar rats, The local distribution of exogenous NGF was demonstrated by immunohistochemical staining. In naive rats, an NGF dose of 84.00 or 16,80 mu g infused into either the cortex or the corpus striatum for 2 weeks caused ipsilateral hypertrophy of the cholinergic neurons of the NBM. In cortically devascularized animals, an NGF dose of 84.00 pg delivered into the cortex and 84.00 mu g or 16.80 mu g infused into the striatum adjacent to the NBM for 2 weeks rescued the ipsilateral cholinergic phenotype of NBM neurons of the basolocortical pathway from retrograde degeneration. Thus, exogenous NGF can affect the cholinergic phenotype of the NBM regardless of whether it is presented to their nerve terminal fields or their somatodendritic region. The present results provide new evidence that the TrkA receptors present in the somatodendritic region of the cholinergic neurons of the NBM are functional and capable of modulating neuronal phenotype in the naive and lesioned CNS,when applied pharmacologically. (C) 1997 Academic Press