Survival and mitogenesis of neuroepithelial cells are influenced by noradrenergic but not cholinergic innervation in cultured embryonic rat neopallium

alpha-Adrenoreceptors are present in the ventricular (VZ) and subventricula r (SVZ) zones of the mammalian embryonic forebrain, and contribute towards cell cycle controls in the germinal neuroepithelium [Pabbathi et al., Brain Res. 760 (1997) 22-33.]. Since noradrenaline-containing fibres from the lo cus coeruleus (LC) and other brainstem nuclei innervate many parts of the C NS from an early stage of embryogenesis, we have used heterochronic cocultu res to investigate whether noradrenergic innervation may be the source of t rophic support. Dorsal neopallium from E13 rat embryo was cultured in proxi mity to E15 rostral pens (RP), enabling rapid innervation of the neuroepith elium by differentiated noradrenergic neurons of the LC. The projection of interconnecting fibres into germinal areas of the cortex was established in vitro by retrograde tracing and dopamine beta-hydroxylase (DBH) immunocyto chemistry. When functional innervation was prevented by transection of axon s connecting the explants, the number of apoptotic (TUNEL-positive) cells i n the neopallium was increased. Bromodeoxyuridine (BrdU) double-labelling c onfirmed that germinal cells were amongst those which underwent apoptosis. When cortical explants were innervated by a source of non-monoaminergic (ch olinergic) axons from the E18 basal forebrain diagonal band/septum complex (DS), numbers of apoptotic cells were comparable to those in non-innervated cultures. alpha 1 and alpha 2 adrenoreceptor antagonists included in the m edium of cortical cocultures innervated by noradrenergic axons reversed the survival-promoting effect of innervation. Blockade of alpha 1 but not of a lpha 2 receptors also reduced the numbers of S-phase nuclei in the cortex. The results provide evidence that local delivery of neurotransmitter from e mbryonic noradrenergic axone terminating in the neocortex can regulate surv ival and proliferation of neuroepithelial cells. (C) 2000 Elsevier Science B.V. All rights reserved.