Astrocytes are an important component of the neuropil and their dysfunction has been associated with a variety of idiopathic and genetic diseases including Alzheimer's and Parkinson's disease and in energy deprivation syndromes such as thiamine deficiency and antimetabolite poisoning. The prevailing model of healthy astrocyte-neuron interaction is one of continuous and intimate physical contact between adjacent membranes that promotes neuronal homeostasis. While the loss of astrocytes in the neuropil is generally viewed as a negative event, we propose here that in the acute phases of intoxication loss of astrocytes may protect neurons against further injury mediated by release of adenosine. Specifically, in this proposal we hypothesize that DNB-induced oxidative stress in astrocytes induces the release of adenosine which in turn activates A1 receptors in neurons via paracrine mechanisms and self-regulates A2 receptors on injured astrocytes. Since oxidative stress is the precipitating event, the corollary to this hypothesis is that in neurons, oxidative stress converges on PI3K/ERK to regulate the activity of BCL proteins that promote mitochondrial fusion and stabilization of the cell. Additional neuronal protection is achieved via A1-mediated activation of AKT with blockage of pro-death Bcl proteins and activation of survival Bcl-proteins. Conversely, in astrocytes, activation of the A2 receptor exacerbates loss of calcium control, swelling and cell death. This hypothesis for the role of astrocytes in the protection of neurons from oxidative stress-induced cell death will be tested by addressing the following specific questions.
AIM 1 : Can adenosine released by astrocytes silence neurons and protect them from the effects of exposure to 1,3-DNB? Aim 2: Does A1 receptor mediated signaling through PI3K, AKT and/or ERK block death- related members of the Bcl-family of proteins in neurons? Aim 3: Is the course of mitochondrial fusion or fission determined by or dependent upon binding of Mfn1/2, Bax/Bad/Bcl-XL and Drp 1? Aim 4: Does binding of proteins that alter mitochondrial morphology also alter membrane potential and function? Dinitrobenzene (DNB) provides and excellent model of energy deprivation syndromes with selective damage to astrocytes. This experimental approach will enable dissection of the role of BCL-proteins, mitofusins and Drp-1 in coordinating the loss of mitochondrial function and may provide new insights into neuronal/glial interactions that form the foundation for pathoclisis, or selective cellular susceptibility to environmental neurotoxicants.
Astrocytes are supporting cells in the central nervous system. Data from our laboratories show that they are a primary target of many environmental chemicals that result in dysfunction of the central nervous system. As injury to the astrocyte progresses, ATP is converted to adenosine and is released into the extracellular space where it can interact with A1 receptors on neurons (protective) and A2 receptors on astrocytes (injurious). We propose here that in the acute phases of CNS injury, loss of neuronal function (silencing) is elicited by adenosine and may spare the neuron from the deleterious effects of oxidative stress and excitotoxicity.
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