Current research projects

Professor Robert Harvey

Professor of Pathophysiology – University of the Sunshine Coast

Professor Robert Harvey’s research interests are centred firmly around Biomedical Science, in particular molecular neuroscience and genetics. Professor Harvey studies receptors and transporters for GABA, glycine and glutamate, using bioinformatics, cellular models, genetics, electrophysiology and molecular modelling to understand how the genetic basis of human and animal disorders.

He is internationally known for his work on startle disease in humans, cattle and dogs, as well as mouse models of glycine receptor dysfunction. The latter revealed roles for the GlyR α2 and α3 subunits in autism spectrum disorder, central pain sensitisation and rhythmic breathing.

Professor Harvey is also the Co-Editor in Chief of the open access journal Frontiers in Molecular Neuroscience.

Current research projects include:

NMDA receptors are key mediators of brain plasticity, converting neuronal activity into long-term changes in synaptic structure and function.

Mutations affecting the GluN2A subunit have recently been identified in focal childhood epilepsies ranging from mild, self-limiting rolandic epilepsy to severe epileptic encephalopathies. By contrast, defects in GluN2B subunit have been linked to West syndrome, intellectual disability, autism and schizophrenia.

We aim to understand how different mutations in GluN2A and GluN2B cause such a wide spectrum of neurological disorders, defining pathogenic mechanisms, exploring new therapeutic avenues and generating new acute mouse models of NMDAR dysfunction (Fedele et al 2018, Nat Comm 9:957).

The aims of this project are to:

  1. Use molecular biology to generate a series of GluN2A and GluN2B missense mutants for analysis in cellular trafficking assays;
  2. Conduct detailed electrophysiological analysis, examining changes in agonist binding, modulation by Zn2+, voltage-sensitive Mg2+ blockade, and changes to kinetics of NMDA currents;
  3. Explore the possibility of developing new treatments for epilepsy, by testing the efficacy of NMDA receptor antagonists and proteostasis regulators on mutant NMDARs.

Key collaborators include: Angelo Keramidas, Joseph Lynch and Rob Capon (University of Queensland, Australia); Manju Kurian (UCL Institute of Child Health, London, UK) and Trevor Smart (UCL Neuroscience, Physiology and Pharmacology, London, UK).

Using subunit-specific antibodies and knockout mice, we have uncovered key biological roles of these ‘minor’ GlyR isoforms. For example, GlyRs containing the α3 subunit are highly expressed in the dorsal horn of the spinal cord and several brainstem nuclei.

This information led to the discovery that α3 subunit knockout mice are defective in prostaglandin (PGE2)-mediated inflammatory pain sensitisation (Harvey et al 2004, Science 304:884-887) and rhythmic breathing (Manzke et al 2010, J Clin Invest 120:4118-4128).

More recently, GlyR α2 has been shown to control cortical neuronal progenitor homeostasis, migration and circuit formation with mild microcephaly, susceptibility to seizures and deficits in long-term potentiation and object recognition memory observed in Glra2 knockout mice (Avila et al 2013, Cell Rep 4:738-750; Avila et al 2014, Cell Death Differ 21:1696-1708; Pilorge et al 2016, Mol Psychiatry 21:936-945; Morelli et al 2017, Cereb Cortex 27:1863-1877).

We are also examining the functions of the expanded GlyR gene family in zebrafish (α1, α2, α3, α4a, α4b, βa and βb), revealing novel movement phenotypes and new mutants with defective glycinergic transmission (Hirata et al 2013, J Neurosci 33:14638-14644; Leacock et al 2018, Front Mol Neurosci 11:23).

Future research aims to:

  1. Characterise additional phenotypes in GlyR α2 and α3 knockout mice at the molecular and behavioural level;
  2. To develop modulators of GlyR α3 function as novel therapeutics for inflammatory pain or breathing disorders and
  3. To use CRISPR/Cas9-mediated gene editing to generate eGFP reporter and knockout lines for the zebrafish GlyR α1, α2, α3, α4a and α4b subunits.

Key collaborators: Trevor Smart (UCL Neuroscience, Physiology and Pharmacology, London, UK), Joe Lynch (University of Queensland, Australia), Hiromi Hirata (Aoyama Gakuin University, Sagamihara, Japan) and Carmen Villmann (Julius-Maximilians-University of Würzburg, Germany).

Dopamine transporter deficiency syndrome (DTDS), also known as infantile parkinsonism-dystonia, is a rare genetic disorder that starts in infancy.

Patients with inactivating mutations in the dopamine transporter gene (SLC6A3) present with an increase in involuntary hyperkinetic movements and dystonia – involuntary spasms and muscle contractions. Later in the disease course, patients develop reduced movement (hypokinesia) with parkinsonian features, such as rigidity and tremor.

Diagnosis is confirmed by cerebrospinal fluid neurotransmitter analysis and genetic analysis of SLC6A3. Currently, there are no treatments that slow or arrest DTDS progression, and most patients die in their early teenage years from pneumonia or breathing problems.

We recently generated a stable zebrafish model of DTDS using CRISPR/Cas9 gene editing technology.  We now aim to:

  1. Quantify levels of dopamine and other transmitters and metabolites in this model using HPLC and fast-scan cyclic voltammetry (FSCV). Here we expect to observe raised ratios of homovanillic acid to 5-hydroxyindoleacetic acid, which are seen in the human disorder.
  2. Assess behaviour in adult DTDS mutants to assess whether they develop a hypokinetic phenotype, or show increased anxiety, hyperactivity or aggression – phenotypes previously linked to alterations in dopamine levels.
  3. Zebrafish DAT mutants will also be used for in vivo drug screening to identify possible new treatments for DTDS. Drugs will be screened for their ability to correct hyperactivity/hypoactivity phenotypes and restore dopamine levels.

Key collaborators: Dr William Norton (University of Leicester, UK) and Jason Rihel (UCL Dept of Cell and Developmental Biology, London, UK).

Recent publications:

  1. Strobbe D, Robinson AA, Harvey K, Rossi L, Ferraina C, de Biase V, Rodolfo C, Harvey RJ, Campanella M (2018) Distinct Mechanisms of pathogenic DJ-1 mutations in mitochondrial quality control. Front Mol Neurosci 11:68.
  2. Fedele L, Newcombe J, Topf M, Gibb A, Harvey RJ*, Smart TG* (2018) Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nat Comm 9:957. *Equal contribution.
  3. Leacock S, Syed P, James VM, Bode A, Kawakami K, Keramidas A, Suster M, Lynch JW, Harvey RJ (2018). Structure/function studies of the α4 subunit reveal evolutionary loss of a GlyR subtype involved in startle and escape responses. Front Mol Neurosci 11:23.
  4. Molchanova SM, Comhair J, Karadurmus D, Piccart E, Harvey RJ, Rigo JM, Schiffmann SN, Brône B, Gall D (2018) Tonically active α2 subunit-containing glycine receptors regulate the excitability of striatal medium spiny neurons. Front Mol Neurosci 10:442.
  5. Schaefer N, Berger A, van Brederode J, Zheng F, Zhang Y, Leacock S, Littau L, Jablonka S, Malhotra S, Topf M, Winter F, Davydova D, Lynch JW, Paige CJ, Alzheimer C, Harvey RJ, Villmann C (2017) Disruption of a structurally important extracellular element in the glycine receptor leads to decreased synaptic integration and signaling resulting in severe startle disease. J Neurosci 37:7948-7961.
  6.  Zhang Y, Ho TNT, Harvey RJ, Lynch JW, Keramidas A (2017) Structure-function analysis of the GlyR α2 subunit autism mutation p.R323L reveals a gain-of-function. Front Mol Neurosci 10:158.
  7. Morelli G, Avila A, Ravanidis S, Aourz N, Neve RL, Smolders I, Harvey RJ, Rigo JM, Nguyen L, Brône B (2017) Cerebral cortical circuitry formation requires functional glycine receptors. Cereb Cortex 27:1863-1877.
  8. Lowrie M, Thomson S, Bessant C, Sparkes A, Harvey RJ, Garosi L (2017) Levetiracetam in the management of feline audiogenic reflex seizures: a randomised, controlled, open-label study. J Feline Med Surg 19:200-206.
  9. Martinez-Hernandez E, Ariño H, McKeon A, Iizuka T, Titulaer MJ, Simabukuro MM, Lancaster E, Petit-Pedrol M, Planagumà J, Blanco Y, Harvey RJ, Saiz A, Graus F, Dalmau J (2016) Clinical and immunologic investigations in patients with stiff-person spectrum disorder. JAMA Neurol 73:714-720.
  10. Wilkins ME, Caley A, Gielen MC, Harvey RJ, Smart TG (2016) Murine startle mutant Nmf11 affects the structural stability of the glycine receptor and increases deactivation. J Physiol 594:3589-3607.
  11. Long P, May MM, James VM, Grannò S, Johnson JP, Tarpey P, Stevenson RE, Harvey K, Schwartz CE, Harvey RJ (2016) Missense mutation R338W in ARHGEF9 in a family with X-linked intellectual disability with variable macrocephaly and macro-orchidism. Front Mol Neurosci 8:83.
  12. Kalscheuer VM, James VM, Himelright ML, Long P, Oegema R, Jensen C, Bienek M, Hu H, Haas SA, Topf M, Hoogeboom AJ, Harvey K, Walikonis R, Harvey RJ (2016) Novel missense mutation A789V in IQSEC2 underlies X-linked intellectual disability in the MRX78 family. Front Mol Neurosci 8:85.
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