Astrocytes Role in Lipid Mediated Synaptic Activity

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neuroscience, 2013.
Astrocytes are a major cell type in both the human and rodent central nervous systems. Due to their inability to be electrically excited, astrocytes have been viewed as supportive cells providing a suitable environment for neuronal signaling without participating in information processing. This simplistic view has been overturned in the past few decades by evidence showing that astrocytes can respond directly to local neuronal activity with subsequent modification. Neurotransmitters such as glutamate can initiate intracellular Ca2+ signaling in astrocytes that leads to astrocyte release of gliotransmitters, including glutamate, D-serine, ATP or endocannabinoids, which can modulate nearby synaptic strength. Moreover, astrocytes release Arachidonic Acid metabolites, such as PGE2, modulating local blood flow to meet the energy demands of increased neuronal activity. 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 calciumindependent 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. We report that upon Ca2+ chelation and receptor stimulation astrocytes can release lipid in a Ca2+ independent manner and that these lipids can indeed affect neuronal signaling. Furthermore, using a model of transient Heterosynaptic Depression (tHSD) in cortical s