Acetyl- l-carnitine has a neuromodulatory influence on neuronal phenotypes during early embryogenesis in the chick embryo

Abstract

Studies from this laboratory and others have demonstrated that neuroblasts in early embryogenesis exhibit a high degree of plasticity with respect to neurotransmitter phenotype. The critical period within which these neuroblasts are sensitive to the effects of endogenous neurotrophins has been defined as 1–3 days of development in the chick embryo. In this study, we examined the influence of acetyl- l-carnitine (ALCAR) administered in ovo during embryonic days 1–3 (E1–E3) and sacrificed at embryonic day 8 (E8) on cholinergic and GABAergic neuronal phenotypes using as neuronal markers the activities of choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD), respectively. Phenotype expression was assessed in 3 distinct anatomical regions of the embryonic brain: cerebral hemispheres (CH), optic lobes (OL), and diencephalon-midbrain-brainstem (DMBS). A single administration of ALCAR at embryonic day 1 resulted in a dose-dependent increase in ChAT activity and decrease in GAD activity in CH. ChAT activity was again increased and GAD activity decreased in CH from embryos that were administered ALCAR (100 μg/50 μl/day) daily from embryonic day E1 to E3. No change was observed in either ChAT or GAD activity in OL in response to ALCAR administration during the critical period (E1–E3) at doses ranging from 10 to 500 μg/day. In the DMBS, the activity of ChAT exhibited a marked increase at lower doses (10 μg) followed by a marked decrease at higher doses (500 μg) of ALCAR. The decrease in ChAT activity in DMBS was again observed at an ALCAR dose of 100 μg/day when administered from E1 to E3. Finally, GAD activity in the DMBS exhibited a dose-dependent decrease which was also apparent when ALCAR was administered in a single dose (100 μg) at E1 or daily from E1 to E3. We interpret these data to suggest that a small molecule such as acetyl- l-carnitine administered during active neuroblast mitosis and neuronal differentiation (E1–E3) differentially effects neuronal phenotypic expression in cholinergic and GABAergic neurons in various regions of the CNS. Thus, in pluripotential neuroblasts, ALCAR shifts expression in favor of the cholinergic phenotype at the expense of GABAergic neurons playing a neuromodulatory role in neuronal plasticity during early neuroembryogenesis.