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Role of Astroglia in Learning and Memory: Insights from NMDA Receptor Function

This article explores the critical role of astroglia in learning and memory, focusing on the interaction with NMDA receptors. It discusses key findings such as the essential release of D-serine from astrocytes for long-term potentiation (LTP) and memory encoding. Additionally, it highlights experiments involving forebrain engraftment of human glial progenitor cells, showing enhanced synaptic plasticity and learning capabilities in adult mice. The mechanisms underlying these enhancements, including calcium wave propagation and TNF's influence on synaptic transmission, are examined.

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Role of Astroglia in Learning and Memory: Insights from NMDA Receptor Function

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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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