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