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Philip Haydon"The Tripartite Synapse: From discovery towards therapies"

Abstract :


Santiago Ramon Y Cajal had numerous great insights into brain function.
Another has recently been realized. In 1895 he proposed that astrocytes, the major subtype of glial cell in the brain, control sleep and waking states. He specifically proposed that astrocytic processes are electrical insulators that, when extended between neurons, act as circuit breakers to facilitate sleep but, when retracted, allow neuronal circuits to communicate, facilitating wakefulness. Now, following work of the past five years we know that his intuition was correct because we have been able to demonstrate that astrocytes regulate the extracellular accumulation of adenosine a factor that is known to control sleep homeostasis.

One of the difficulties with identifying the roles of astrocytes in the regulation of synaptic transmission, circuits and behavior is that pharmacological studies do not allow a discrimination of glial versus neuronal mechanisms of actions. The explosion of mouse molecular genetics is beginning to give new insights into the role of astrocytes in brain and behavior. In 2005 we demonstrated that astrocytes regulate adenosine. In this study conditional, astrocyte specific molecular genetics were used to inhibit the release of bioactive compounds from astrocytes. In this study the SNARE domain of synatptobrevin 2 was expressed in adult astrocytes. By expressing this construct, the formation of the core SNARE complex that is required for exocytosis was prevented. In a control experiment we asked whether basal hippocampal synaptic transmission was modulated through glial expression of dnSNARE. Surprisingly we found that the magnitude of CA3-CA1 synaptic transmission was augmented, and that the mechanism was mediated by the removal of a tonic presynaptic inhibition that is normally mediated by basal extracellular adenosine acting on presynaptic A1 receptors.

In addition to effects on synaptic plasticity, we have discovered that the astrocytic source of adenosine is essential for the process of sleep homeostasis and for responses to sleep deprivation. Sleep can be considered to be controlled by at least two processes: the circadian oscillator that sets the timing of sleep and wakefulness, and the sleep hemostat that integrates the amount of wakefulness and promotes the drive to sleep. Astrocytic adenosine is critical for the control of sleep homeostasis. When an animal sleeps the power of slow wave activity (SWA) during non rapid eye movement (NREM) sleep is proportional to sleep drive. Thus, when one is sleep deprived, the power of the SWA is increased in propotion to the sleep debt that was incurred. When EEG and EMG recordings were performed from dnSNARE mice we found that the power of SWA during NREM sleep was significantly attenuated at the onset of the sleep period. Additionally, on a subsequent day, sleep deprivation caused an attenuated increase in the power of SWA in astrocytic dnSNARE mice. Another consequence of sleep deprivation is that there is compensatory increase in sleep time. Surprisingly, astrocytic dnSNARE mice did not exhibit altered sleep times following sleep deprivation. These effects of astrocytic dnSNARE expression were phenocopied in wild type mice by intracerebroventricular administration of the A1 receptor antagonist CPT indicating that these glia, as suggested by Cajal, exert powerful control over sleep.

Of great interest in our current studies is whether the glial modulation of sleep homeostasis contribute to disorders of brain function? So many brain disorders exhibit sleep co-morbidities. Depressed patients either sleep too little or too much. Bipolar patients exhibit a limited need to sleep during mania. Do inactivated glia contribute to these psychiatric conditions? Recovering alcoholics exhibit highly fragmented sleep and this sleep fragmentation is the most reliable predictor of relapse. Additionally, sleep deprivation increases the probability of breakthrough seizures in epileptic patients. While we do not propose that glia are the cause of all of these disorders, our current work is examining the roles of astrocytes in these disorders and we are asking whether we can develop new therapeutics for these disorders based on emerging knowledge of glial-based targets.

Selected publications

Lee SY, Haydon PG. 2011. A cytokine-dependent switch for glial-neuron interactions. Neuron 69: 835-837.
Halassa MM, Dal Maschio M, Beltramo R, Haydon PG, Benfenati F, Fellin T. 2010. Integrated brain circuits: neuron-astrocyte interaction in sleep-related rhythmogenesis. Scientific World J 17: 1634-1645.
Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA. 2010. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nature Neurosci. 13: 584-591.

Dong J, Revilla-Sanchez R, Moss S, Haydon PG. 2010. Multiphoton in vivo imaging of amyloid in animal models of Alzheimer's disease. Neuropharmacology 59: 268-275.
Fellin T, Halassa MM, Terunuma M, Succol F, Takano H, Frank M, Moss SJ, Haydon PG. 2009. Endogenous nonneuronal modulators of synaptic transmission control cortical slow oscillations in vivo. Proc Natl Acad Sci USA 106: 15037-15042.

Scientific focus :

Philip G. Haydon joined the Department of Neuroscience as a professor and chair in 2008. He studies astrocytes, those glial cells found throughout the central nervous system that were once thought to be merely structural (glia is Greek for glue) but are now thought to participate actively in neural transmission. Haydon is excited about obtaining a deeper understanding of astrocytes, for basic neuroscience as well as potential therapeutics.

Haydon earned his PhD in physiology from the University of Leeds, England, and pursued postdoctoral training in biology at the University of Iowa. As a faculty member at Iowa State University, he was director of the Signal Transduction Training Group and the Laboratory of Cellular Signaling, and he was associate director of the Microanalytical Instrumentation Center. While a member of the Department of Neuroscience at the University of Pennsylvania, Haydon directed the Center for Dynamic Imaging of Nervous System Function and the Silvio O. Conte Center for Studies of the Tripartite Synapse

Maurice Garret et Stéphane Oliet