Cholinergic neurons are the first neurons to die during Alzheimer's disease. As a consequence therapeutic strategies to treat the early cognitive symptoms of this disease have included cholinesterase inhibitors; in fact a positive allosteric modulator of the a7 nicotinic acetylcholine receptor (a7n-AChR) has recently entered phase III clinical trials. How these cognitive enhancing therapies achieve therapeutic benefit is unclear; however, data suggest that there is an important downstream modulation of NMDA receptor (NMDAR) function. Our preliminary data lead us to postulate that cholinergic activity, acting through the astrocytic a7n-AChR, modulates the release of astrocyte-derived D-serine, which in turn acts on the co-agonist site of the NR1 subunit of the NMDAR to augment NMDAR function. According to this hypothesis the well-known night/day time alterations in cholinergic activity drive oscillations in D-serine accumulation and thus NMDAR function. We have four specific aims to test our hypothesis.
Aim I : Is the amount of D-serine available to synaptic NMDARs regulated by a sleep-homeostasis mechanism? Aim II: What are the physiological and behavioral consequences of daily fluctuations of D-serine availability? Aim III: Does an astrocytic source of D-serine contribute to wakefulness dependent regulation of D-serine? Aim IV: Does astrocytic a7n-AChRs drive wakefulness dependent modulation of D-serine? To achieve these aims we will use brain slice electrophysiology and amperometric biosensors in situ as well as in vivo recordings of D-serine. In addition to performing studies in wild type mice we will use molecular genetics to make cell type specific manipulations of gliotransmission and of the a7n-AChR and will use astrocyte specific optogenetics to selectively stimulate the release of D-serine from this glial cell sub-type. Defining the role of nicotinic receptor modulation of astrocyte-derived D-serine, and the consequent effects on NMDARs, synaptic plasticity and behavior, will provide new insights into the mechanisms of action of cholinergic therapeutics and will provide a new opportunity to understand the regulation of D-serine, a critical co-agonist of the NMDAR.
Defining the role of nicotinic receptor modulation of astrocyte-derived D-serine, and the consequent effects on NMDARs, synaptic plasticity and behavior, will provide new insights into the mechanisms of action of cholinergic therapeutics and will provide a new opportunity to understand the regulation of D-serine, a critical co-agonist of the NMDAR.
| Papouin, Thomas; Haydon, Philip G (2018) D-serine Measurements in Brain Slices or Other Tissue Explants. Bio Protoc 8: |
| Papouin, Thomas; Haydon, Philip G (2018) Obtaining Acute Brain Slices. Bio Protoc 8: |
| Haydon, Philip G (2017) Astrocytes and the modulation of sleep. Curr Opin Neurobiol 44:28-33 |
| Clasadonte, Jerome; Scemes, Eliana; Wang, Zhongya et al. (2017) Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle. Neuron 95:1365-1380.e5 |
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| Keck, Tara; Toyoizumi, Taro; Chen, Lu et al. (2017) Integrating Hebbian and homeostatic plasticity: the current state of the field and future research directions. Philos Trans R Soc Lond B Biol Sci 372: |
| Papouin, Thomas; Dunphy, Jaclyn M; Tolman, Michaela et al. (2017) Septal Cholinergic Neuromodulation Tunes the Astrocyte-Dependent Gating of Hippocampal NMDA Receptors to Wakefulness. Neuron 94:840-854.e7 |
| Clasadonte, Jerome; Morel, Lydie; Barrios-Camacho, Camila M et al. (2016) Molecular analysis of acute and chronic reactive astrocytes in the pilocarpine model of temporal lobe epilepsy. Neurobiol Dis 91:315-25 |
| Haydon, Philip G (2016) The Evolving View of Astrocytes. Cerebrum 2016: |
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