A ROLE FOR TRKA DURING MATURATION OF STRIATAL AND BASAL FOREBRAIN CHOLINERGIC NEURONS IN-VIVO

Nerve growth factor (NGF), acting via the TrkA receptor, has been show n to regulate the survival and maturation of specific neurons of the p eripheral nervous system. Furthermore, exogenous NGF has potent action s on TrkA-expressing cholinergic neurons of the basal forebrain (BFCNs ) and striatum. However, initial analysis of mice lacking NGF or TrkA revealed that forebrain cholinergic neurons were present in these anim als through the fourth postnatal week. Because of the potential effect s of NGF/TrkA interactions on these developing neurons, we have analyz ed quantitatively the striatal and basal forebrain cholinergic neurons in trkA knock-out mice. By postnatal day (P) 7/8, forebrain cholinerg ic neurons are smaller in trkA (-/-) mice than those in wild-type litt ermate controls. However, cholinergic neuron number and fiber density in the hippocampus, a target region of BFCNs, are grossly intact. Inte restingly, by P20-P25 trkA knock-outs contain significantly fewer (20- 36%) and smaller cholinergic neurons in both the striatum and septal r egions, as compared with controls. Cholinergic fiber density within th e hippocampus also is depleted in knock-outs by the end of the second postnatal week. Contrary to some predictions, despite expression of p7 5(NTR) in the absence of trkA in BFCNs of these knock-out mice, many c ells, although smaller, are still alive at P25. Our data suggest that, in the absence of NGF/TrkA signaling, striatal cholinergic neurons an d BFCNs do not mature fully and that BFCNs begin to atrophy and/or die surrounding the time of target innervation.