The lab is based at the Neuroscience and Mental Health Research Institute at Cardiff University. We use a combination of electrophysiology, 2-photon imaging and optogenetic and computational approaches to study the function of dendrites, synapses and neural networks in physiology and disease.
The lab has three current major research themes:
- Dendritic and circuit integration in cortico-thalamocortical circuits
- Dendritic and synaptic dysfunction in neurodevelopmental disorders
- Extrasynaptic GABAA receptors
Dendritic and Circuit Integration in Cortico-thalamocortical Circuits
Sensory signals carrying information about the external environment are transmitted to the cortex and continuously and dynamically integrated with our internal cognitive model that underlies our perception of the world, The majority of these signals, with the noted exception of the olfactory system, first pass through a structure called the thalamus. For many years, it was thought that the thalamus acted to simply ‘relay’ peripheral signals in a machine like fashion to higher cortical networks with little, if any, information processing occurring at the thalamic level. Recently, it has become clear that this assumption is inaccurate and that neurons in thalamocortical circuits are intimately involved in information processing, critical brain rhythms and several disease states including epilepsy and schizophrenia. In fact, cortico-thalamamocortical circuits are extremely complex and thalamic circuits involving glutamatergic thalamocortical neurons, local circuit interneurons and GABAergic neurons of the thalamic reticular nucleus (TRN) have key functions. Indeed, it is increasingly recognised that, because of the strong bidirectional connectivity between them, the thalamus and cortex cannot be considered in isolation but should but thought of as two parts of the same dynamic circuit that have powerful influences on each other. Our research focuses on the intrinsic and dendritic integrative properties of key neurons within these circuits and the role that cortical feedback to thalamic nuclei play in modulating sensory information flow through thalamic microcircuits. Using 2-photon fluorescence targeted patch clamp we have performed the first direct electrical recordings from the very thin dendrites of excitatory glutamatergic thalamocortical neurons and inhibitory GABAergic neurons of the thalamic reticular nucleus.
Dendritic Dysfunction in Neurodevelopmental Disorders
A number of human genetic variations that confer high risk for developing neurodevelopmental disorders such as schizophrenia and autism spectrum disorder have been identified by genome-wide association studies (GWAS) in recent years. In particular, changes to large sections of DNA, known as copy number variations (CNVs), that result in insufficient or excessive numbers of copies of certain genes have been strongly linked to severe disease phenotypes. Many CNVs contain genes that have been identified to code for proteins that are highly involved in cellular excitability, in particular a number of key synaptic targets. Furthermore, a number of disease associated genetic changes (e.g. DISC-1, NRG-1, Dysbindin, Cyfip-1) have been strongly linked to pronounced changes in dendritic structure of cortical and hippocampal pyramidal neurons including changes in dendritic length, the number of dendritic branches and differences in the type, density and distribution of dendritic spines. Abnormalities in dendritic structure and in dendritic spines have long been recognised as critical hallmarks of a number of neurodevelopmental disorders. Using a range of models our research focuses on how specific genetic changes contribute to changes in dendritic structure, function and synaptic integration and how this might contribute to disruption of normal brain circuit function in neuropsychiatric diseases.
Extrasynaptic GABAA Receptors
γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the brain and its actions are mediated by two diverse families of neurotransmitter receptors, the ionotropic receptors, known as GABAA receptors, and metabotropic receptors that are classified as GABAB receptors. The classical phasic inhibitory postsynaptic potential (IPSP) is mediated by GABAA receptors that are located in the postsynaptic membrane. However, GABA also produces tonic inhibition through activation of GABAA receptors that are located outside the synapse. These extrasynaptic GABAA receptors respond to low concentrations of GABA to provide more spatially and temporally diffuse inhibition compared to their synaptic counterparts.