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
-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

23. Fig 3

24. Fig 4

25. Fig 5

26. 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

27. Fig 6

28. 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