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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 - PowerPoint PPT Presentation
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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
• “Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice”▫Han et al
Themes
•Long Term Potentiation
•Learning
•The Glia/NMDA Relationship
•What makes humans so damn special?
Long Term Potentiation
Excitatory Post-Synaptic Potential
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
NMDA Receptor
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
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
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
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
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?
Fig 1
Fig 2
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
Fig 3
Fig 4
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
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
Fig 1
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
Fig 3
Fig 4
Fig 5
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
Fig 6
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