Local injection of antisense oligonucleotides targeted to the glial glutamate transporter GLAST decreases the metabolic response to somatosensory activation

The mechanisms responsible for the local increase in brain glucose utilizat ion during functional activation remain unknown. Recent in vitro studies ha ve identified a new signaling pathway involving an activation of glial glut amate transporters and enhancement of neuron-astrocyte metabolic inter-acti ons that suggest a putative coupling mechanism. The aim of the present stud y was to determine whether one of the glutamate transporters exclusively ex pressed in astrocytes, GLAST, is involved in the neurometabolic coupling in vivo. For this purpose, rats were microinjected into the posteromedial bar rel subfield (PMBSF) of the somatosensory cortex with GLAST antisense or ra ndom phosphorothioate oligonucleotides. The physiologic activation was perf ormed by stimulating the whisker-to-barrel pathway in anesthetized rats whi le measuring local cerebral glucose utilization by quantitative autoradiogr aphy in the PMBSF. Twenty-four hours after injection of two different antis ense GLAST oligonucleotide sequences, and despite the presence of normal wh isker-related neuronal activity in the PMBSF, the metabolic response to whi sker stimulation was decreased by more than 50%. Injection of the correspon ding random sequences still allowed a significant increase in glucose utili zation in the activated area. The present study highlights the contribution of astrocytes to neurometabolic coupling ill. vivo. It provides evidence t hat glial glutamate transporters are key molecular components of this coupl ing and that neuronal glutamatergic activity is an important determinant of energy utilization. Results indicate that astrocytes should also be consid ered as possible sources of altered brain metabolism that could explain the distinct imaging signals observed in some pathologic situations.