Associate Professor Stephen Williams - Synaptic integration in neural networks

Research directions

Our aim is to understand the cellular and network operations of the neocortex. Using state of the art multi-site electrophysiological and optical recording techniques, we explore, at the single cell level, how electrical signals spread throughout the complex dendritic tree of neurons and, at the network level, the dynamics of synaptic transmission between groups of neurons and multimodal integration in long-range intracortical circuits. We integrate this information using neuron-inspired network simulations to gain an understanding of network function. Our research is divided into four main themes:

Synaptic Integration: A single neuron in the central nervous system may receive thousands of synaptic inputs distributed widely across its dendritic arbor. A fundamental operation of neurons is the integration of such time varying input signals to form an output signal, termed the action potential, which is communicated to other neurons and/or effector systems such as muscles. We investigate key questions of single neuron computation by generating diverse spatial and temporal patterns of synaptic inputs in central neurons maintained in vitro. We use advanced electrophysiological and optical techniques that allow simultaneous recording from multiple dendritic sites of a single neuron, the uncaging of neurotransmitters at identified dendritic sites and the optical activation of neuronal pathways expressing light-activated channels to explore synaptic integration strategies in neurons of diverse morphology.

Network dynamics: Neocortical pyramidal neurons are embedded in active neuronal networks that fire spontaneous and stimulus-evoked patterns of action potentials in the working brain. How effectively are physiological firing patterns transmitted through excitatory synaptic connections in the neocortex? We have shown that the synapses of the output neurons of the neocortex code information on an action potential-by-action potential basis. These synapses showed increased neurotransmitter release in response to short high frequency trains of action potentials, suggesting that bursts of action potentials are an important unit of information in the neocortex. Recently, we have precisely recreated action potential firing patterns recorded from neocortical neurons in vivo, to investigate how physiological patterns of activity are transmitted through different classes of excitatory synaptic contacts in vitro. We find that excitatory synaptic transmission between neocortical pyramidal neurons in response to physiological firing patterns is pathway-specific. Layer 2/3 to layer 5 responses were dominated by synaptic depression, transmitting only the onset of physiological firing patterns. In contrast, layer 5 to layer 5 excitatory synapses faithfully transmitted each action potential of the physiological train. We suggest that the intra-cortical synaptic output of layer 5 pyramidal neurons is ideally suited to dynamically control the cortical network on an action potential-by-action potential basis across a wide range of frequencies and for sustained periods of time, providing a reliable internal representation of neocortical output.

Single neuron computation: Multi-site whole-cell recordings from the dendrites of principal neurons of the rodent neocortex, thalamus, substantia nigra and cerebellum have allowed insight into the role of dendritic mechanisms in neuronal computation. For example, in cortical pyramidal neurons, the most abundant neuronal class in the neocortex, work has shown that synaptic conductance is uniform for excitatory synapses positioned throughout the apical dendritic tree. Excitatory postsynaptic potentials (EPSPs) generated from distal dendritic sites therefore have a negligible impact at the level of the soma, a site close to the axonal site of action potential initiation. We find, however, that distal dendritic EPSPs can be locally integrated in the dendritic tree, to trigger powerful dendritic spikes that robustly forward propagate through the dendritic arbor to drive neuronal output. This form of compartmentalised synaptic integration was found to be robust under conditions that mimic active states in the working brain. Moreover, we find that under conditions of ongoing action potential firing, the recruitment of dendritic sodium and calcium voltage-activated channels greatly amplify the impact of barrages of distal dendritic EPSPs, providing a conditional mechanism for the normalization of synaptic efficacy. Taken together, these findings reveal that dendritic mechanisms extend the computational repertoire of single neurons.

Ion channel targeting: We have identified that classes of voltage-activated ion channels are non-uniformly distributed through the dendritic tree of neurons and that specific somato-dendritic expression patterns of ion channels are a signature of neurons from different brain regions. For example, we were the first to describe the highly polarized apical dendritic distribution of Hyperpolarization-activated Cyclic Nucleotide gated (HCN) channels in neocortical pyramidal neurons and show the important function of this channel type in controlling the spatio-temporal integration of dendritically generated synaptic potentials.

Students interested in a rigorous and mechanistic study of the central nervous system are encouraged to apply directly to the lab.
  

Current collaborations

The group actively collaborates with Dr. Jeff Magee and Dr. Mark Harnett using multi-site 2-photon uncaging techniques to study synaptic integration in central neurons. This collaboration has been made possible by the visiting scientist programme at the Howard Hughes Medical Institute Janelia Farm Research Campus, USA.

Selected publications

ETHERINGTON, S.J. & WILLIAMS, S.R. (2011). Postnatal development of intrinsic and synaptic properties transforms signaling in the layer 5 excitatory neural network of the visual cortex. Journal of Neuroscience, 29, 9526-37.

ATKINSON, S.E., MAYWOOD, E.S., CHESHAM, J.E., WOZNY, C., COLWELL, C.S., HASTINGS, M.H. & WILLIAMS, S.R. (2011). Cyclic AMP signaling controls action potential firing rate and molecular circadian pacemaking in the suprachiasmatic nucleus. Journal of Biological Rhythms, 26, 210-220.

WILLIAMS, S.R. & WOZNY, C. (2011). Errors in the measurement of voltage-activated ion channels in cell-attached patch-clamp recordings. Nature Communications, 2:242, doi: 10.1038/ncomms1225.

WOZNY, C. & WILLIAMS, S.R. (2011). Specificity of synaptic connectivity between layer 1 inhibitory interneurons and layer 2/3 pyramidal neurons in the rat neocortex. Cerebral Cortex, doi: 10.1093/cercor/bhq257.

WILLIAMS, S.R. & WOZNY, C. (2009). Neuroscience: The chain reaction of dendritic integration. Current Biology, 19, pR956.

ATKINSON, S.E. & WILLIAMS, S.R. (2009). Postnatal development of dendritic synaptic integration in rat neocortical pyramidal neurons. Journal of Neurophysiology, 102, 735-751.

WILLIAMS, S.R. & ATKINSON, S.E. (2008). Dendritic synaptic integration in central neurons. Current Biology, 18, R1045-R1047.

PENN, A.C., WILLIAMS, S.R. & GREGER, I.H. (2008). Gating motions underlie AMPA receptor secretion from the endoplasmic reticulum. EMBO Journal, 19, 3056-3068.

WILLIAMS S.R. & MITCHELL, S.J. (2008). Direct measurement of somatic voltage clamp errors in central neurons. Nature Neuroscience, 11, 790-798.

KOLE, M.H.P., ILSCHNER S.U., KAMPA, B.M., WILLIAMS, S.R., RUBEN, P.C. & STUART, G.J. (2008). Action potential generation requires a high sodium channel density in the axon initial segment. Nature Neuroscience, 11, 178-186.

WILLIAMS, S.R., WOZNY. C. & MITCHELL, S.J. (2007). The back and forth of dendritic plasticity. Neuron, 56:947-953.

WILLIAMS, S.R & ATKINSON, S.E. (2007). Pathway-specific use-dependent dynamics of excitatory synaptic transmission in rat intra-cortical circuits. Journal of Physiology, 585, 759-777.

GENTET, L.J. & WILLIAMS, S.R. (2007). Dopamine gates action potential backpropagation in midbrain dopaminergic neurons. Journal of Neuroscience, 27; 1892-1901.

WILLIAMS, S.R. (2005). Encoding and decoding of dendritic excitation during active states in pyramidal neurons. Journal of Neuroscience, 22; 5894-5902.

WILLIAMS, S.R. (2004). Spatial compartmentalization and functional impact of conductance in pyramidal neurons. Nature Neuroscience, 7, 961-967.

WILLIAMS, S.R. & STUART, G.J. (2003). Voltage- and site-dependent control of the somatic impact of dendritic IPSPs. Journal of Neuroscience, 23, 7358-7367.

WILLIAMS, S.R. & STUART, G.J. (2003). Role of dendritic synapse location in the control of action potential output. Trends in Neurosciences, 26(3), 147-154.

CRUNELLI, V., BLETHYN, K.L., COPE, D.W., HUGHES, S.W., PARRI, H.R., TURNER, J.P., TÓTH, T.I. & WILLIAMS, S.R. (2002). Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics. Phil. Trans. R. Soc. Lond. B. 357, 1675-1693.

WILLIAMS, S.R. & STUART, G.J. (2002). Dependence of EPSP efficacy on synapse location in neocortical pyramidal neurons. Science, 295, 1907-1910.

WILLIAMS, S.R., CHRISTENSEN, S.R., STUART, G.J. & HÄUSSER M. (2002). Membrane potential bistability is controlled by the hyperpolarization-activated current IH in rat cerebellar Purkinje neurons in vitro. Journal of Physiology, 539, 469-483.

WILLIAMS, S.R. & STUART, G.J. (2000). Backpropagation of physiological spike trains in neocortical pyramidal neurons: Implications for temporal coding in dendrites. Journal of Neuroscience, 20, 8238-8246.

WILLIAMS, S.R. & STUART, G.J. (2000). Site independence of EPSP time course is mediated by dendritic IH in neocortical pyramidal neurons. Journal of Neurophysiology, 83, 3177-3182.

WILLIAMS, S.R. & STUART, G.J. (2000). Action potential backpropagation and somato-dendritic distribution of ion channels in thalamocortical neurons. Journal of Neuroscience, 20, 1307-1317.

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