Synaptic transmission in the brain

FEdwards1
Dr Frances Edwards
Reader in Neurophysiology
Tel: +44 20 7679 3286 (Lab 3254)
Email: f.a.edwards@ucl.ac.uk
Iris Profile and all publications

Lab Members:

Dr Damian Cummings, MRC Postdoc Iris Profile d.cummings@ucl.ac.uk

Dr Dervis Salih, Alzheimer's Research UK Senior Research Fellow Iris Profile dervis.salih@ucl.ac.uk

Dr Marina Yasvoina, MRC Postdoc  m.yasvoina@ucl.ac.uk

Ms Rivka Steinberg, MRC Research Assistant

Statistical Advisor

Dr Lion Shahab, Dept Epidemiology & Public Health, UCL Iris Profile lion.shahab@ucl.ac.uk

Honorary Research Assistant

Shabinah Ali

PhD Students:

Zelah Joel

Tiffanie Benway

Joshua Paulin

Wenfei Liu

MSc Students 2014-2015

Fabia Moroni

Patricia Pascual Vargas

Funding:

MRC; EPSRC, Alzheimer's Research UK; GlaxoSmithKline; Eisai

Collaborators

Professor John Hardy, Dr. Mar Matarin, Professor Kenneth Smith IoN, UCL

Professor Francesca Cordeiro, IoO, UCL

Professor Sir Mark Pepys, Royal Free Hospital

Professor Mark Lythgoe, CABI, UCL

Professor Stephen Hart, ICH, UCL

Professor Kaj Blennow and Dr Erik Portelius, Univ Gothenburg Sweden

Professor Henrik Zetterberg, IoN UCL & Univ Gothenburg Sweden

Dr Frances Edwards


Dr Frances Edwards graduated in Pharmacology at the University of Sydney, Australia and received her PhD whilst working at the Max-Planck Institute in Germany under the Nobel Prize winner, Prof. Bert Sakmann.

After staying on as a postdoctoral fellow in Sakmann's lab, in 1990 she joined David Colquhoun’s group in Pharmacology at UCL as a Wellcome European Fellow.

After returning to Australia in 1992 Frances held a Queen Elizabeth II Research Fellowship at the University of Sydney from 1993 until 1996.

In 1996 she joined the Department of Physiology at UCL. Until 2010 the focus of the Edwards lab was mechanisms of fast synaptic transmission and the role of dendritic spines in plasticity using electrophysiology and confocal imaging.

In 2010 the research direction largely shifted to research on Alzheimer's disease, studying several transgenic mouse models of human mutations in the amyloid pathway or microtubule-associated protein tau.

The approaches have expanded to include a range of molecular biology and immunohistochemical techniques and genetics (in collaboration with John Hardy).

The effects of rising Abeta in Alzheimer’s disease

Alzheimer’s disease occurs when the ability to control the laying down and/or retrieval of memory is disturbed.

We hypothesise that this is related to early damage to one or more of the pathways that the brain can choose to use for plasticity and homeostasis.

By comparing synaptic transmission, plasticity and morphology in a range of mouse models with genes for Alzheimer’s disease or prefrontal dementia, we aim to find distinct or common deficits in the network that would decrease the flexibility for change.

By concentrating on early stages of the disease at the time when cognitive deficits are first detected we hope, in collaboration with GSK and Eisai, to find useful targets for future drug development.

Understanding gene expression changes throughout the progression of pathology in different mice models informs the direction of research.

Mouse Genome-wide gene expression: synapses and the immune system

[www.mouseac.org]

Mouse Genome-wide gene expression


Figure legend: CD68 (red) positive microglia are activated and surround Aβ-42 (green) plaques in 12 month old mice expressing human APP and PSEN1 containing mutations found in patients with familial Alzheimer’s disease (HE, heterozygous; HO, homozygous). Counterstained with DAPI (blue). Scale: 50μm

In collaboration with the Hardy lab we have undertaken a genome-wide analysis of gene expression in 5 lines of mice that are transgenic for genes that cause dementia (and WT mice) throughout the development of the Alzheimer's disease-like phenotype and in 3 different brain regions.

This gives us an invaluable resource to guide our electrophysiological, immunohistochemical and molecular biology studies of these mice.

In addition to the synaptic studies, this has led us into studies of the immune system and neuronal pentraxins.

Processing of Memory in Health and Disease: Plasticity and Homeostasis in the Hippocampus

Memory must involve activity-dependent changes in the network of communication between brain cells.

The hippocampus has long been known to be involved in the laying down of memory and much work on this field has concentrated on this area of the brain.

Moreover this is one of the first areas to show changes in Alzheimer’s disease. Cellular phenomena have been described by which the communication at individual synapses (the connections between individual neurones) can be strengthened ('long-term potentiation', LTP) or weakened ('long-term depression', LTD).

But should the changes in the hippocampus really last indefinitely? If strengthening or weakening of synapses in a particular pathway are uncontrolled this could result in imbalance of the overall output of the neurone so that it fires too fast or insufficiently to maintain healthy function and processing.

Such imbalances can be very damaging, not only undermining the intended function of the circuit and so impairing learning but also resulting in conditions such as epilepsy.

As change in synaptic strength is integral to the very function of the hippocampus, this region will be particular vulnerable to such problems.

In order to avoid such imbalance, the neurones are known to have strong balancing (homeostatic) mechanisms.

A lot of past work has focused on such homeostasis but generally by studying the effects of weakening or strengthening all the synapses of the neurones measured, using pharmacological means.

Instead we directly visualise changes in the synapses (De Simoni et al., 2006) as specialising in high resolution electrical recording between individual neurones or recording of plasticity in the network.

We can thus strengthen or weaken the synapses within one pathway and study what happens to them and their neighbours over time.

We particularly take advantage of recent findings which have demonstrated a close correlation between the strength and the size of individual synapses.

Thus we combine direct recording of synaptic transmission using patch clamp techniques in brains slices with measurement of synapse size.

Electrophysiological recording


Figure legend: An example of electrophysiological recording (from Parsley et al., 2007). Unitary evoked glutamatergic synaptic currents recorded with patch clamp techniques from a mouse hippocampal CA1 neurone. CA3 axons were stimulated by placing an electrode extracellularly in the Stratum Radiatum and gradually increasing the voltage of a short (50 μs) pulse. At 4V a synaptic response is seen putatively due to stimulation of a single axon. This response stays constant until the voltage reaches 6V when more axons start to be recruited.


Imaging neurones: GFP mice

Using mice expressing GFP, we are able to image the changes in dendritic spines under different conditions in organotypic or acute slices and understand the relation between synaptic plasticity, morphology and homeostasis.

3-D modelling of dendritic spines

Figure legend: 3D modelling of dendritic spines of hippocampal pyramidal neurones expressing GFP using Imaris software.

Methods

· Brain slices: Acute and cultured (organotypic) slices of rodent hippocampus and/or cortex

· Cultures of dissociated hippocampal neurones and of cell lines

· Electrophysiology measurement of synaptic currents using patch clamp or field recording in acute and cultured brain slices

· Genome-wide microarray studies and bioinformatics to identify genetic pathways related to synapse function during health and disease

· Molecular biology for knock-down and overexpression of genes of interest especially in relation to Alzheimer's disease

· Immunohistochemistry

· Confocal microscopy for detailed dendritic and spine analysis, and immunohistochemistry

Recent & Selected Publications

Witton J, Padmashri R, Zinyuk LE, Popov VI, Kraev I, Line SJ, Jensen TP, Tedoldi A, Cummings DM, Tybulewicz VL, Fisher EM, Bannerman DM, Randall AD, Brown JT, Edwards FA, Rusakov DA, Stewart MG, Jones MW (2015) Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome. Nat Neurosci. 2015 Aug 3. doi: 10.1038/nn.4072. Epub ahead of print [PubMed]

Cummings DM, Liu W, Portelius E, Bayram S, Yasvoina M, Ho SH, Smits H, Ali SS, Steinberg R, Pegasiou CM, James OT, Matarin M, Richardson JC, Zetterberg H, Blennow K, Hardy JA, Salih DA, Edwards FA (2015) First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression. Brain. 2015 Jul;138(Pt 7):1992-2004. doi: 10.1093/brain/awv127. Epub 2015 May 16 [PubMed]


Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, Nahaboo Solim MA, Moens TG, Paublete RM, Ali SS, Perona M, Desai R, Smith KJ, Latcham J, Fulleylove M, Richardson JC, Hardy J & Edwards FA. (2015) A Genome-wide Gene-Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology. Cell Reports 10(4):633-44. [PubMed]. Fully searchable database of the genome-wide microarray data can be accessed at [www.mouseac.org]

Shahab L, Plattner F, Irvine EE, Cummings DM & Edwards FA. (2014) Dynamic range of GSK3α not GSK3β is essential for bidirectional synaptic plasticity at hippocampal CA3-CA1 synapses. Hippocampus 24(12):1413-6. [PubMed]

Alfarez DN, De Simoni A, Velzing EH, Bracey E, Joëls M, Edwards FA & Krugers HJ. (2009) Corticosterone reduces dendritic complexity in developing hippocampal CA1 neurons. Hippocampus 19(9):828-36. [PubMed]

Donato R, Rodrigues RJ, Takahashi M, Tsai MC, Soto D, Miyagi K, Gomez Villafuertes R, Cunha RA & Edwards FA. (2008) GABA release by basket cells onto Purkinje cells, in rat cerebellar slices, is directly controlled by presynaptic purinergic receptors, modulating Ca2+ influx. Cell Calcium 44:521-32. [PubMed]

Parsley SL, Pilgram SM, Soto F, Giese KP & Edwards FA. (2007) Enriching the environment of αCaMKIIT286A mutant mice reveals that LTD occurs in memory processing but must be subsequently reversed by LTP. Learning & Memory 14, 75-83. [PubMed]

Donato R, Miljan EA, Hines S, Aouabdi S, Pollock K, Patel S, Edwards FA & Sinden JD. (2007) Differential development of neuronal physiological responsiveness in two human neural stem cell lines. Biomed Central Neuroscience 8:36. [PubMed]

De Simoni A & Edwards FA. (2006) Pathway specificity of dendritic spine morphology in identified synapses onto rat hippocampal CA1 neurons in organotypic slices. Hippocampus 16(12), 1111-24. [PubMed]

Donato R, Page KM, Koch D, Nieto-Rostro M, Foucault I, Davies A, Wilkinson T, Rees M, Edwards FA & Dolphin AC. (2006) The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression. Journal of Neuroscience 26, 12576-86. [PubMed]

De Simoni A, Fernandez F & Edwards FA. (2004) Spines and dendrites cannot be assumed to distribute dye evenly, Trends in Neuroscience 27, 15-16. [PubMed]

De Simoni A, Griesinger CB, Edwards FA. (2003) Development of rat CA1 neurones in acute vs. organotypic slices: role of experience in synaptic morphology and activity. Journal of Physiology 550, 135-148. [PubMed]

Dean I, Robertson SJ & Edwards FA. (2003) Serotonin drives a novel GABAergic synaptic current recorded in rat cerebellar Purkinje cells: a Lugaro cell to Purkinje cell synapse. Journal of Neuroscience 23, 4457-4469. [PubMed]

Price GD, Robertson SJ & Edwards FA. (2003) Long-term potentiation of glutamatergic synaptic transmission induced by activation of presynaptic P2Y receptors in the rat medial habenula nucleus. European Journal of Neuroscience 17, 844-850. [PubMed]

Robertson SJ, Ennion SJ, Evans RJ & Edwards FA. (2001) Synaptic P2X receptors. Current Opinion in Neurobiology 11, 378-386. [PubMed]

Robertson SJ, Burnashev N & Edwards FA. (1999) Ca2+ permeability and kinetics of glutamate receptors in rat medial habenula neurones: implications for purinergic transmission in this nucleus. Journal of Physiology 518, 539-549. [PubMed]

Edwards FA & Robertson SJ. (1999) The function of A2 adenosine receptors in the mammalian brain: evidence for inhibition vs enhancement of voltage gated calcium channels and neurotransmitter release. Progress in Brain Research, 120, 265-273. [PubMed]

Cooper EJ, Johnston GAR & Edwards FA. (1999) Effects of a naturally occurring neurosteroid on GABAA IPSCs during development in rat hippocampal or cerebellar slices. Journal of Physiology, 521, 437-449. [PubMed]

Robertson SJ & Edwards FA. (1998) ATP and glutamate are released from separate neurones in the rat medial habenula nucleus: frequency dependence and adenosine-mediated inhibition of release Journal of Physiology, 508, 691-701. [PubMed]

Edwards FA. (1998) Dancing dendrites. Nature (News & Views) 394:129-130 [PubMed]

Edwards FA, Robertson SJ & Gibb AJ. (1997) Properties of ATP receptor-mediated synaptic transmission in the rat medial habenula. Neuropharmacology 36, 1253-1268. [PubMed]

Edwards FA. (1995) Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. Physiological Reviews 75: 759-787. [PubMed]

Edwards FA. (1995) LTP - a structural model to explain the inconsistencies. Trends in Neuroscience 18, 250-255. [PubMed]

Gibb AJ, Edwards FA (1994) Patch clamp recording from cells in sliced tissues. In: Microelectrode techniques: The Plymouth Workshop handbook, (Ogden D, Ed), pp 255-274 The Company of Biologists Limited, Cambridge.

Edwards FA & Gibb AJ. (1993) ATP - A fast neurotransmitter FEBS Letters 325: 86-89. [PubMed]

Edwards FA, Gibb AJ & Colquhoun D. (1992) ATP receptor-mediated synaptic currents in the central nervous system. Nature 359: 144-146. [PubMed]

Stern P, Edwards FA & Sakmann B. (1992) Fast and slow components of unitary EPSCs on stellate cells elicited by focal stimulation in slices of rat visual cortex. Journal of Physiology, 449: 247-278. [PubMed]

Edwards FA & Konnerth A. (1992) Patch-clamping cells in sliced tissue preparations. Methods in Enzymology 207: 208-222. [PubMed]

Edwards FA. (1992) Long-term potentiation: Miniatures get bigger. Nature (News and Views) 355: 21-22. [Nature PDF]

Edwards FA. (1991) LTP is a long-term problem. Nature (News and Views) 350: 271-272. [Nature PDF]

Edwards FA, Konnerth A & Sakmann B. (1990) Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: a patch-clamp study. Journal of Physiology 430: 213-249. [PubMed]

Burnashev NA, Edwards FA & Verkhratsky AN. (1990) Patch-clamp recordings on rat cardiac-muscle slices. Pflügers Archiv 417, 123-125. [PubMed]

Sakmann B, Edwards FA, Konnerth A & Takahashi T. (1989) Patch clamp techniques used for studying synaptic transmission in slices of mammalian brain. Quarterly Journal of Experiemntal Physiology and Cognate Medical Sciences 74: 1107-1118. [PubMed]

Edwards FA, Konnerth, A, Sakmann B & Takahashi T. (1989). A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system. Pflügers Archiv 414, 600-612. [PubMed]

Edwards FA & Gage PW. (1988) Seasonal changes in inhibitory currents in rat hippocampus Neuroscience Letters 84: 266-270. [PubMed]