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

Lab Members:

  • Dr Damian Cummings
  • Dr Dervish Selih

Postgraduate Students:

  • Tiffanie Benway
  • Peter Haslehurst
  • Zelah Joel
  • Joshua Paulin
 

Funding:

GlaxoSmithKline; BBSRC and Marie Curie Foundation via CORTEX (CM and MM)

Collaborators

  • Dr Martin Stocker, UCL
  • Jill Richardson and Dr Elena DiDaniel, GlaxoSmithKline
  • Dr Harm Krugers, Professor Marion Joels University of Amsterdam

FAE

Dr Frances Edwards graduated in Pharmacology at the University of Sydney, Australia and received her PhD in 1990 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 1990 she joined David Colquhoun’s lab 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 as a Senior Lecturer and was promoted in 1999 to Reader in Neurophysiology. Since 1999 she has run the MSc Neuroscience. Frances is on the Editorial Board of Biomed Central Neuroscience.

Processing of Memory; 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 unbalance 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 use methods we have recently developed (De Simoni et al., 2006) as well as other recently introduced techniques such as microelectrode arrays which allow us to stimulate individual pathways impinging on the hippocampal CA1 pyramidal cell. 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.

FEdwards3

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 ms) 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.

FEdwards2

Hippocampal CA1 pyramidal neuronel in an organotypic slice of rat brain. Left Panel: The postsynaptic cell is filled with Alexa 594 via the patch electrode which can be seen on the left of the main picture. Crystals of DiO have been placed in the CA3 region. This lipophillic dye dissolves in the membrane and travels down the axons so that green axons seen in the CA1 region are known to have originated in the CA3 region. Middle panel: Single scans of a and b (labelled in main picture) showing the close apposition of the presynaptic bouton and postsynaptic spines. Right panel 3D reconstruction of deconvolved z-series of synapses shown in a and b

Mouse models of 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 which the brain can choose to use for plasticity and homeostasis. By comparing synaptic transmission, plasticity and morphology in a range of mouse models of Alzheimer’s disease, we aim to find common deficits in the network which 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, to find useful targets for future drug development.

Methods

Our main approaches involve:

  • Brain slices Acute and cultured (organotypic) slices of rodent hippocampus and/or cortex
  • Electrophysiology Measurement of synaptic currents using patch clamp or field recording in acute and cultured brain slices (Edwards et al., 1989)
  • Imaging Confocal microscopy is used for detailed dendritic and spine analysis.

Full publication list with PDFs

Selected Publications

(total citations ~3100)

  • 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
  • Donato, R., Rodrigues, R.J., Takahashi, M., Tsai, M.C., Soto, D., Miyagi, K., Gomez Villafuertes, R., Cunha, R.A., Edwards, F.A.(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
  • Parsley, S.L., Pilgram, S.M., Soto, F, Giese, K.P. & Edwards, F.A. (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
  • Donato R, Miljan E.A., Hines S, Aouabdi S, Pollock K, Patel S, Edwards FA and Sinden J.D. (2007) Differential development of neuronal physiological responsiveness in two human neural stem cell lines. Biomed Central Neuroscience 8:36
  • De Simoni A and Edwards F.A.(2006) Pathway specificity of dendritic spine morphology in identified synapses onto rat hippocampal CA1 neurons in organotypic slices. Hippocampus 16, 1111-24.
  • 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. J Neurosci. 26, 12576-86
  • De Simoni, A., Fernandez, F., Edwards, F.A. (2004) Spines and dendrites cannot be assumed to distribute dye evenly, Trends in Neuroscience 27, 15-16
  • De Simoni, A., Griesinger, C.B. & Edwards, F.A. (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
  • Dean, I., Robertson, S.J. & Edwards, F.A. (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
  • Price, G.D., Robertson, S.J. & Edwards, F.A. (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
  • Robertson, S.J., Ennion, S.J., Evans, R.J. and Edwards, F.A. (2001) Synaptic P2X receptors. Current Opinion in Neurobiology, 11, 378-386
  • Robertson, S.J., Burnashev, N., & Edwards, F.A. (1999) Glutamate Receptor properties of neurones which receive fast P2X synaptic inputs in the rat medial habenula. Journal of Physiology 518, 539-549
  • Edwards, F.A. & Robertson, S.J. (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
  • Cooper, E.J., Johnston, G.A.R. & Edwards, F.A. (1999) Effects of a naturally occurring neurosteroid on GABAA IPSCs during development in rat hippocampal or cerebellar slices. Journal of Physiology, 521, 437-449
  • Robertson, S.J. & Edwards, F.A. (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
  • Edwards, F.A. (1998) Dancing dendrites. Nature (News & Views) 394:129-130
  • Edwards, F.A., Robertson, S.J. & Gibb, A.J. (1997) Properties of ATP receptor-mediated synaptic transmission in the rat medial habenula. Neuropharmacology 36, 1253-1268
  • Edwards, F.A. (1996) Features of P2X receptor-mediated synapses in the rat brain: why doesn't ATP kill the postsynaptic cell? CIBA Foundation Symposium 198, Wiley
  • Edwards, F. A. (1995) Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation Physiological Reviews 75: 759-787
  • Edwards, F.A. (1995) LTP –– a structural model to explain the inconsistencies. Trends in Neuroscience 18, 250-255
  • 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 F.A. & Gibb A.J. (1993) ATP - A fast neurotransmitter FEBS Letters 325: 86-89
  • Edwards, F.A., Gibb, A.J. Colquhoun, D. (1992) ATP receptor-mediated synaptic currents in the central nervous system. Nature 359: 144-146
  • Stern, P., Edwards, F.A., & 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.
  • Edwards, F.A., Konnerth, A. (1992) Patch-clamping cells in sliced tissue preparations. Methods in Enzymology 207: 208-222
  • Edwards, F.A. (1992)Long-term potentiation- miniatures get bigger Nature (News and Views) 355: 21-22
  • Edwards, F. (1991) LTP is a long-term problem Nature (News and Views) 350: 271-272
  • Edwards, F.A., Konnerth, A. and 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
  • Burnashev N.A., Edwards, F.A., Verkhratsky, A.N. (1990) Patch-clamp recordings on rat cardiac-muscle slices. Pflugers Archive 417, 123-125
  • Sakmann B, Edwards F, Konnerth A, Takahashi T. (1989) Patch clamp techniques used for studying synaptic transmission in slices of mammalian brain Quarterly J. Exp. Physiology and cognate medical sciences 74: 1107-1118
  • Edwards, F. A., Konnerth, A., Sakmann, B., & Takahashi, T. (1989). A thin slice preparation for patch clamp recordings from neurones of the mammalian central nervous system. Pflugers Archives 414, 600-612
  • Edwards F.A. & Gage P.W. (1988) Seasonal changes in inhibitory currents in rat hippocampus Neuroscience Letters 84: 266-270