Dr Andrew Pocklington

Publication

• Date
• Type

Research

My work to date has identified neurodevelopmental pathways and components of the mature synaptic signalling machinery whose perturbation contributes to schizophrenia aetiology. Disruption of these same processes plays a role in other neuropsychiatric disorders. I am currently pursuing several lines of fundamental and translational research that build on these findings (below). Broadly speaking, my long-term research plans are centred around the following questions:

1.  What are the cellular pathways regulating neuronal development and diversification?
2. Which developmental/mature cell-types are disrupted in neuropsychiatric disorders?
3. How does disruption of cell-types/cellular pathways map onto behavioural symptoms?
4. Can modulation of pathways in mature cell-types rescue cellular/circuit level deficits?

Fundamental research

Neurodevelopmental pathways in health and disease
I have become increasingly interested in unravelling the cellular processes regulating brain development and the diversification of excitatory and inhibitory neurons into specialised sub-types. The birth of neurons during CNS development is a sequential process involving the generation of progressively more specialised cell-types. Proliferating neuroectodermal cells in the neural tube give rise to neural precursors (NPCs): radial glia (RG) and intermediate progenitors (iPCs). Both RG and iPCs have a limited ability to proliferate, with RG giving rise to neurons either directly or via iPCs. Studies to date indicate that neuronal identity is determined by the internal state of NPCs immediately prior to their exit from the cell-cycle, with changes in this state over time leading to the progressive generation of different sub-types. However, the cellular pathways regulating this process remain unclear.

In collaboration with the stem-cell neurobiology group of Dr Jenny Shin we have begun to map out these pathways and investigate the extent to which they are disrupted across a wide spectrum of neuropsychiatric disorders; this work utilises the in vitro differentiation of human pluripotent stem cells to model neurodevelopment. Our recent study uncovered coordinated waves of gene expression regulating the growth and development of deep layer cortical excitatory neurons; it also revealed these transcriptional programs to be highly enriched for common and rare genetic variants conferring risk for neuropsychiatric disorders. Following on from this we are now analysing single-cell gene expression time-course data from the in vitro differentiation of multiple cortical inhibitory interneuron sub-types. In addition to this work I collaborate with the developmental neurobiology group of Prof Beatriz Rico, who utilise rodent model systems to investigate the role of interneuron development in schizophrenia with a particular focus on synaptogenesis.

Cell-type specificity in neuropsychiatric genetic disorders
Each aspect of behaviour arises from activity within a unique constellation of local neuronal circuits distributed across a network of brain regions. The computational properties of these circuits are determined by the neuronal sub-types of which they are composed: their abundance, connectivity and history of past activity as encoded in their internal state. In order to understand the role of genetic variants in generating the behavioural symptoms associated with a given neuropsychiatric disorder, we need to know which neuronal sub-types they affect; the functional properties they perturb in these sub-types; and the computational role(s) these properties play in the function of neuronal circuits and networks underlying specific behaviours.

My interest in the molecular basis of neuronal specificity and behaviour arose through an early study with the group of Prof Seth Grant; we showed that while mouse brain regions express a similar set of postsynaptic proteins, the levels of upstream signalling/structural components (e.g. receptors and closely associated scaffolding molecules) varied most between regions. This suggests that the precise expression of these molecules plays an important role in shaping the computational and cognitive properties of the brain. Genetic studies by ourselves and others robustly implicate the disruption of postsynaptic signalling (including individual channels and receptors) in disorders such as schizophrenia. This indicates that neuropsychiatric disorders are likely to involve the widespread disruption of brain function, with any one risk variant impacting multiple behavioural traits. My group is currently utilising single-cell expression data to explore the relative impact of genetic risk factors on different neuronal sub-types.

Refining disease-relevant biology via network analysis
Our ability to determine the precise cellular pathways disrupted in disease is limited by the resolution of existing biological data. For example, proteomic studies have revealed the molecular composition of a number of synaptic components: presynaptic neurotransmitter release vesicles, postsynaptic receptor-linked signal transduction complexes, etc. Using these data I was able to show that the constituents of postsynaptic NMDA receptor complexes (NRCs) are enriched for rare variants found in individuals with schizophrenia, implicating disruption of NRCs in the disorder. NRCs couple the NMDA receptor to multiple downstream signalling pathways whose activation plays a major role in regulating the induction of synaptic plasticity at excitatory synapses. This raises the question: does schizophrenia involve widespread disruption of NRC functioning, or is it associated with the perturbation of one or more specific signalling pathways within NRCs? We have previously shown that direct, physical interactions (protein-protein interactions, PPIs) organise NRC proteins into functionally distinct sub-units, shaping the computational properties of these complexes. Building on this, we can ask whether there are subsets of interacting proteins (functionally relevant subnetworks) that are more highly enriched for disease association than the NRC as a whole.

Such techniques are widely applicable. My group is using subnetwork identification methods to analyse both gene-regulatory and synaptic protein networks. The work on synaptic networks is being carried out in collaboration with the group of Prof Douglas Armstrong, who have curated a large body of PPI data for synapse proteins.

Translational research

Prioritising candidate genes for drug development
Existing medications are effective in controlling the psychotic symptoms of schizophrenia for many individuals. However, they do not treat the negative (e.g. anhedonia, social withdrawal, apathy) and cognitive symptoms of the disorder which have a major impact on quality of life. The development of more effective treatments has been extremely challenging, with relatively little progress in the past 60 years. A major factor contributing to this has been our limited understanding of disease mechanisms, which has made it virtually impossible to rationally select biological targets (molecules, pathways, cell-types) whose manipulation will impact one or more aspect of the disorder. Common and rare variant studies increasingly have power to generate insight into disease aetiology and are now starting to robustly identify schizophrenia risk genes. Drawing together the various strands of fundamental research outlined above, my group is seeking to uncover the cell types and biological pathways within which these risk genes operate and use this information to identify potential molecular targets for the development of novel therapeutics. This is being pursued through collaboration between Cardiff University and Takeda Pharmaceutical Company Ltd.

Biography

Following a degree in Mathematical Physics (BSc, Hons 1^st class) at the University of Edinburgh and a PhD in Theoretical Physics at the University of Durham, I spent several years as a post-doctoral researcher in Japan and Brazil. Becoming increasingly interested in the emerging fields of bioinformatics and systems biology, I returned to the University of Edinburgh where I obtained an MSc in Informatics, specializing in bioinformatics and graduating with distinction. In 2003 I was awarded an MRC Special Research Training Fellowship in Bioinformatics to study the functional organisation of the synapse proteome and its role in behaviour and disease, analysing much of the molecular neuroscience data generated by the Genes to Cognition (G2C) research programme at the Wellcome Trust Sanger Institute. In 2009 I was appointed Senior Lecturer in Bioinformatics at the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University.

Academic positions

• 2009-present    Senior Lecturer in Bioinformatics
                              MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, UK
• 2007-2009       Postdoctoral Research Fellow
                              University of Edinburgh and G2C (Wellcome Trust Sanger Institute), UK
• 2003-2007       MRC Special Research Training Fellow in Bioinformatics
                              University of Edinburgh, UK
• 2000-2001       Postdoctoral Research Fellow
                              Instituto de Física Teórica, UNESP, São Paulo, Brazil
• 1998-2000      JSPS Research Fellow
                             Yukawa Institute of Theoretical Physics, Kyoto, Japan