Observations in our lab have demonstrated that vasodilation is seemingly dissociable from astrocytic calcium dynamics in many cases, thus prompting us to test whether astrocytes through lipid release can signal on a faster signaling scale in a calcium-independent manner. Thus far, virtually all studies looking at astrocytic signaling mechanisms focus on intracellular Ca2+, which is on a signaling time scale of seconds. However, astrocytes are capable of Ca2+ independent signaling that is potentially on a time scale one to two orders of magnitude faster (msec). In line with this, astrocytes possess Ca2+ -independent PLA2 that can lead to the production of AA in the absence of calcium. However, further investigation is needed to reveal the existence of Ca2+-independent signaling from astrocytes and whether this can influence physiological function. To that end, I will in Aim 1 study the hypothesis that astrocytes can release AA and/or its metabolites in a Ca2+ independent manner. Specifically, I will use cultured rat astrocytes to assess receptor stimulated release of lipids in the absence of increases in cytosolic calcium.
In Aim 2, I will use a model of Transient Heterosynaptic Depression (tHSD) to study astrocyte-neuronal signaling in intact hippocampal tissue. I will first assess the role of lipid signaling in tHSD focusing on rapid events occurring on the time-scale of msec. Combined, the proposed studies will provide novel insight into the controversial role of astrocytes in synaptic regulation and thereby in higher information processing. More specifically, because the role of astrocytes in lipid signaling is poorly understood, this proposal will address the mechanism and kinetics of release, as well as it putative function in tHSD.
The proposed studies will explore a novel mechanism of calcium independent astrocytic lipid signaling modulation of synaptic activity. Furthermore, since lipids are known to play an important role in many pathophysiological disorders such as epilepsy, these studies may also give new insight into the role that astrocytes play in neurological disease. Illuminating the importance of this novel lipid signaling mechanism may reveal pathways suitable for pharmacological manipulation to treat diseases of the central nervous system.
|Rangroo Thrane, Vinita; Thrane, Alexander S; Plog, Benjamin A et al. (2013) Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain. Sci Rep 3:2582|
|Rangroo Thrane, Vinita; Thrane, Alexander S; Wang, Fushun et al. (2013) Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. Nat Med 19:1643-8|
|Wang, Fushun; Smith, Nathan A; Xu, Qiwu et al. (2012) Astrocytes modulate neural network activity by Ca²+-dependent uptake of extracellular K+. Sci Signal 5:ra26|
|Lovatt, Ditte; Xu, Qiwu; Liu, Wei et al. (2012) Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity. Proc Natl Acad Sci U S A 109:6265-70|