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 subventricular (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 locus coeruleus (LC) and other brainstem nuclei innervate many parts of the CNS from an early stage of embryogenesis, we have used heterochronic cocultures to investigate whether noradrenergic innervation may be the source of trophic support. Dorsal neopallium from E13 rat embryo was cultured in proximity to E15 rostral pons (RP), enabling rapid innervation of the neuroepithelium 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) immunocytochemistry. When functional innervation was prevented by transection of axons connecting the explants, the number of apoptotic (TUNEL-positive) cells in the neopallium was increased. Bromodeoxyuridine (BrdU) double-labelling confirmed that germinal cells were amongst those which underwent apoptosis. When cortical explants were innervated by a source of non-monoaminergic (cholinergic) axons from the E18 basal forebrain diagonal band/septum complex (DS), numbers of apoptotic cells were comparable to those in non-innervated cultures. alpha1 and alpha2 adrenoreceptor antagonists included in the medium of cortical cocultures innervated by noradrenergic axons reversed the survival-promoting effect of innervation. Blockade of alpha1 but not of alpha2 receptors also reduced the numbers of S-phase nuclei in the cortex. The results provide evidence that local delivery of neurotransmitter from embryonic noradrenergic axons terminating in the neocortex can regulate survival and proliferation of neuroepithelial cells.