213 BDNF Over-Expression and Catecholaminergic Control of Breathing

Abstract

Adaptations to the environmental modifications are important for the survival of the adult and the newborn who may be exposed to physiopathological hypoxemia. Neonate who died from Sudden Infant Death Syndrome present long-term hypoxemic symptoms. The response to the hypoxic stimulus needs the intervention of structures that all together act as a reflex called chemoreflex loop. Carotid bodies (main sensors of the arterial PaO2 decrease), the Nucleus Tractus Solitarius and the sympatho-adrenal pathway, constitute the cardio-respiratory sympathetic chemoreflex loop. Each step of the reflex needs a large number of neurotransmitters. However, all structures are catecholaminergic. Furthermore, in the newborn, the activity of peripheral arterial chemoreceptors is very low or even non-existent at birth, then the next few days this activity starts to emerge and allows the young animal to start to respond to hypoxic exposure. In the carotid body, two factors play an important role in its maturation, dopamine, an inhibitory modulator that down-regulates the maturation, and BDNF that up-regulates the maturation. BDNF is involved in the targeting and the survival of the chemoafferent nerves of the carotid body in the brainstem. We have built a transgenic mouse over-expressing BDNF in the neural stem cell during the development in order to study the catecholamine/BDNF relation in the maturation process. Here we present the effect of a BDNF over-expression on the catecholaminergic activity in the carotid bodies, petrosal ganglion and sympathetic ganglion. We also analyzed the breathing pattern in the newborn mice in normoxic and hypoxic conditions. The transgenic mice are over-expressing BDNF under the Nestin second intron (enhancing sequence). The second intron directs the nestin expression exclusively in the nervous system. The in vivo tyrosine hydroxylase ( the rate limiting enzyme in catecholamine synthesis) activity was determined in the different structures by measuring by chromatography the endogenous DOPA accumulation after blockade of DOPA decarboxylase with NSD 1015.The ventilatory response to hypoxia in awake and unrestrained mice was studied by barosensible plethysmography. The catecholaminergic activity was preferentially increased in the carotid body of the transgenic mice. When challenging the transgenic animals to hypoxia, we observed a different time course in the response. The transgenics reach quicker the plateau. Our preliminary results confirm a tight relation between BDNF expression and the level of maturation in the control of breathing.