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Blood Oxygenated Level Dependent functional Magnetic Resonance Imaging (BOLD fMRI) and Local Field Potentials in the hippocampus of mice lacking IP3-dependent calcium signalling in astrocytes

Non-invasive brain imaging techniques, as functional magnetic resonance imaging (fMRI), allow us to study cognitive functions in humans, but at the same time, they are emerging as powerful diagnostic tools for neurological and psychiatric disorders. Despite their importance, the physiological and cellular mechanisms underlying fMRI signal generation are not well understood. Astrocytes are well known since Santiago Ramon y Cajal's work to be located in tight contact between neurons and brain blood vessels and due to its strategic positioning they were consider as putative transductors of neuronal activity into vascular responses. With the concept of the tripartite synapse at the end of the 90's a renewed interest emerged on understanding the contribution of astrocytes to neurotransmission and synaptic plasticity (Araque et al.,1999). Proportionally less attention has received its role in regulating vascular responses to neuronal activity, the so called neuro-vascular coupling. In 2003, Zonta et al., showed in vitro that after synaptic activation astrocytes uptake extracellular glutamate initiating calcium signaling cascade that finally translated into arteriole dilation. In 2006, Metea and Newman showed that an inositol-1,4,5-triphosphate (IP3) injection into astrocytes, that mobilize calcium from intracellular stores, is enough to dilate artificially constricted vessels in retina slices. These findings, together with previous evidence demonstrating the important role of IP3-dependent calcium signaling in astrocytes for neuronal transmission and plasticity, supported the hypothesis that astrocytes, indeed, were playing a key role in neurovascular coupling. An important caveat of these studies, however, is that they were mainly performed in vitro, experimental conditions in which the energy metabolic substrates are provided ad libitum in the artificial cerebrospinal fluid and the vascular system is devoid of pressure and function. Consequently, it appears necessary to study neuro-glio-vascular coupling in vivo. To this end, genetically modified mice for the subtype 2 of the IP3 receptor (specific for astrocytes) have been created. We used functional Magnetic Resonance Imaging (fMRI) and Blood Oxygenated Level Dependent (BOLD) signal, which permits to visualize neuronal activation through local hyperemia, during electrical Perforant Path stimulation. In parallel, we measure Local Field Potential within the hippocampus during the very same stimulation. We found that IP3 dependent calcium waves in astrocytes are not necessary to neurovascular coupling, nor to initiate the vasodilation neither to maintain it. More surprisingly, we found that synaptic transmission in IP3R2 KO mice hippocampus is slightly weaken during a long stimulation. These results suggest that neurovascular coupling is mediated by a mechanism independent of astrocyte internal calcium stores in vivo. These same calcium stores probably play a role in synaptic strength, maybe by decreasing uptake and/or release of neuro or gliotransmitters.