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Astroglia and Learning

Astroglia and Learning. As Demonstrated in Adult Mice. James M. Robertson. Papers. “NMDA Receptors and Memory Encoding” Morris “Long Term Potentiation Depends on Release of D-Serine from Astrocytes” Henneberger , Papouin , Oliet , Rusakov

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Astroglia and Learning

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  1. Astroglia and Learning As Demonstrated in Adult Mice James M. Robertson

  2. Papers • “NMDA Receptors and Memory Encoding” • Morris • “Long Term Potentiation Depends on Release of D-Serine from Astrocytes” • Henneberger, Papouin, Oliet, Rusakov • “Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice” • Han et al

  3. Themes • Long Term Potentiation • Learning • The Glia/NMDA Relationship • What makes humans so damn special?

  4. Long Term Potentiation • “A long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously” • Wikipedia • http://www.dnatube.com/video/216/LongTerm-Potentiation-LTP

  5. Excitatory Post-Synaptic Potential

  6. Synaptic Plasticity • The ability of synapses to strengthen or weaken over time • Due to use, or the lack thereof • LTP  Synaptic Plasticity  Learning • Occurs through action and modulation of NMDA Receptors

  7. NMDA Receptor

  8. NMDA Receptors and Memory Encoding • 1983 – Collingridge et al blocks induction of LTP between two areas of brain • Pointed to a structural foundation for the basis of learning • Spurred interest in glutamatergic system • 1986 – Morris performs behavioural experiments using NMDA antagonist AP5 • Affirmed that AP5 blocks induction of LTP, not expression

  9. NMDA Receptors and Memory Encoding • 1999 – Steele and Morris study effect of intrahippocampal AP5 on rat behavior in delayed match-to-place (DMP) test • More sensitive than spatial memory test • Suggested NMDA receptor-dependent plasticity in the hippocampus is critical for episodic memory

  10. NMDA Receptors and Memory Encoding • NMDA Subunit KO • Technological advancement brought the possibility of simply impairing the NMDA receptors • 1996 – Tsien et al showed impaired learning potential in hippocampal KO mice

  11. NMDA Receptors and Memory Encoding • NMDA Confusions • Don’t call it a learning receptor • They’re just the sites where the current gets fiddled with (Ca2+, Mg2+) • NMDA Future • Cognitive Enhancement? Hmm…. • PS, don’t give your children ketamine

  12. Long Term Potentiation Depends on Release of D-Serine from Astrocytes • NMDA receptors in the hippocampus are vital for LTP  Memory/Learning • How? • D-serine, NMDAR co-agonist • Comes from glial cells • Ca2+ dependent release • D-serine shown to enable LTP in culture • How will clamping Ca2+ to astroglia affect nearby synapses?

  13. Fig 1

  14. Fig 2

  15. Long Term Potentiation Depends on Release of D-Serine from Astrocytes • Clamping of Ca2+ totally suppressed LTP at nearby synapses • D-Serine addition fully rescued it • No effect in controls • LTP induction = NMDAR co-agonist activation • Then less of the activation site should block LTP

  16. Fig 3

  17. Fig 4

  18. Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice • Humans have big fancy brains • Well, some of us do • We also have big fancy astrocytes, more so than other animals • Suggests an expanded role in neural processing during our evolution

  19. Forebrain Engraftment by Human Glial Progenitor Cells • Established role of Glia in LTP and Learning • So Han decided to stick some human cells in a mouse’s brain • Generated chimeric mice • Human Glia spread through hippocampus, neocortical layers • Wanted to see effect on LTP, Memory, Learning

  20. Fig 1

  21. Forebrain Engraftment by Human Glial Progenitor Cells • Human Astrocytes coupled with those of mice • Still retained structural differences • Enhanced ability to propagate calcium waves • Enhanced excitatory synaptic transmission in hippocampus • Enhanced LTP

  22. Fig 3

  23. Fig 4

  24. Fig 5

  25. Forebrain Engraftment by Human Glial Progenitor Cells • What’s causing all of this abnormal enhancement in the mouse’s abilities? • D-Serine? • Found that TNF was more likely what was strengthening synaptic transmission in chimeric mice • Responsible for greater learning potential as well

  26. Fig 6

  27. Take Home Messages • LTP  Synaptic Plasticity  Learning • NMDA receptors modulate LTP • Therefore affect learning potential • Astroglia regulate actions of NMDA receptors • D-Serine often thought to be mode of regulation • TNF may be more important • Thalidamide (TNF antagonist) canceled LTP effects of human glial cells in chimeric mice

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