Prof Nigel C Jones is head of the Epilepsy & Behaviour Laboratory in the Department of Neuroscience, School of Translational Medicine, Monash University. Specialising in discovery science techniques with a focus on neuro-behavioural, electrophysiological, molecular and neuropharmacological approaches, Prof Jones has made critical and sustained contributions understanding disease pathogenesis to the fields of epilepsy, cognition, schizophrenia and depression research, primarily using small animal models. The primary focus of his laboratory aims to uncover the neurobiological relationships between epilepsy and its associated psychiatric disturbances and developing novel disease-modifying strategies for these complex diseases. He is an energetic neuroscientist with a broad collaborative network with a passion for understanding the basis of neurological dysfunction in brain diseases and identifying new therapeutic opportunities using today’s technologies.

Prof Jones’ contributions to science consist of exploration of neurobiological mechanisms of brain dysfunction, as it pertains to clinically relevant brain conditions. His publication track record includes 168 scientific articles (H-index =54, total cites >8800) in peer-reviewed journals, as well as 2 book chapters. In particular, he has made substantial contributions to three primary scientific domains, as follows:

1. Interrelationships between stress and epilepsy

It has been appreciated for centuries that patients with epilepsy also suffer from debilitating psychiatric disorders such as depression, which severely impact the quality of life of patients. However, the biological mechanisms underpinning this relationship is mysterious and multifactorial. My seminal works have characterized behavioural dysfunction in models of both acquired (eg: PMIDs: 17999745; 19397932; 31335966) and genetic (18022621; 25879152; 19167503; 20153428; 25377760) forms of epilepsies, works which align well with clinical observations, and establish that there must be a biological causation to the psychiatric comorbidities in epilepsy, at least in part. I have constructed several critical review articles on this theme (eg: 19838325, 21165736; 23099287; 25266701) and presented this at international symposia, including at the American Epilepsy Society (2012-6). I also led the AES/ILAE taskforce to produce official guidelines for testing behavioural outcomes in models of epilepsy (30450484). To explore common causal mechanisms, I studied how environmental impacts can influence epilepsy development, identifying that negative environments, such as stressors, accelerate epileptogenesis and magnify disease severity (eg: 17999745; 22749310; 21957442; 24636509), whereas positive environments, including environmental enrichment, retard epileptogenesis and improve behavioural comorbidities (eg: 26786278; 27185593). In seminal work, we identified hyperactivity of the HPA axis as the mechanism responsible for the enduring consequences of early life stress on epileptogenesis (24636509). Subsequent work has explored the influence of antidepressants on epilepsy development: contrary to expectations, SSRI antidepressants accelerate disease development, an effect which does not seem to be due to 5-HT_2A receptors (23146067; 29858497). These works highlight the work of my laboratory establishing the powerful and consistent influence of environmental factors on epilepsy development in a range of models and suggests that caution must be taken when prescribing antidepressants to patients at risk of developing epilepsy.

2. Identifying disease-modifying therapies for epilepsy, targeting neurodegenerative pathways

I have been exploring the mechanisms which explain why patients with neurodegenerative disorders, including Alzheimer’s disease (AD), have increased tendency to develop epilepsy. The hypothesis is that pathologies which are implicated in AD can also lead to hyperexcitability within neuronal networks, and susceptibility to epilepsy. Using established models of AD, including Tg2576 (PMID: 25879152) and 5xFAD (39737719), my lab demonstrated markedly enhanced susceptibility to seizures, supporting this hypothesis. We have expanded this to identify several potential biological mechanisms, including alterations in the enzymes GSK-3 (32456185) and GLT-1 (33971019; 39497295) as playing pivotal roles in epilepsy sensitivity. In parallel, I have explored AD pathologies, such as Aβ plaques and tau tangles (34595752), as a causal mediator of disease in non-AD related epilepsy. A particular focus has been on tau, the intracellular protein which when hyperphosphorylated, causes neurofibrillary tau tangles. I was the first to identify abnormally phosphorylated tau in models of epilepsy (22182692), also present in human TLE patients (34595752). From these reports, I have now gone on to demonstrate the causal role pathological tau plays in the development of epilepsy, utilizing both pharmacological (27289302, 25771151) and genetic approaches (28710841). Finally, and most recently, we developed a novel neuromodulation strategy called GENUS (39737719) – to be employed in the current program. We showed this intervention, potentially through enhancing glymphatic clearance, is able to reduce susceptibility of transgenic AD mice to epileptogenesis.

3. Exploring functional consequences of NMDA receptor hypofunction, with relevance to schizophrenia

The NMDAr hypofunction theory of schizophrenia posits that loss of function of NMDA receptors disrupts neuronal network communication, leading to a ‘fractured mind’. We have been using pharmacological approaches and transgenic animal models to explore the mechanisms by which loss of this receptor leads to behavioural states related to schizophrenia. The focus of this work utilizes electrophysiology - we were the first to characterize the influence of NMDA receptor antagonists on high frequency neural oscillations, observable on the EEG (PMIDs: 19707548; 28676240). Ketamine and MK801 both marked increase spontaneous gamma oscillations, and this is the same neural signature observed in patients with schizophrenia, and remarkably similar to several transgenic animal models used to study this disorder (25992564; 28925523, 30517689). My subsequent works characterized the ability of antipsychotics to suppress elevations in gamma oscillations (21733235; 24964190; 27093066), with the atypical antipsychotic Clozapine showing unique properties (27093066). This work promoted gamma oscillations as a biomarker of drugs which can impact treatment-resistant symptoms. Of key interest to my lab has been to associate these aberrant neural oscillations with behavioural deficits associated with schizophrenia (24832766, 28183030). We have now advanced our behavioural repertoire, studying sophisticated cognitive paradigms, such as attention and working memory (32330470; 31786371, 32658524; 31580222). Subsequent works are exploring the cellular and network mechanisms of how NMDA receptor deficiency disrupts gamma oscillations (27261525; 40374854), whether this neural abnormality itself leads to cognitive deficits, and can we harness this to develop novel treatments.