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 “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
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?
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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
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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
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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
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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
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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