Small molecules that restore GABAergic function as a potential therapeutics to treat Autism Spectrum Disorder
Please note rescheduled date.
A cardinal feature of human brain development is that sensory, cognitive, and emotional experiences shape synapses and neural-circuit development. Neuronal activity triggers changes at the synapse, altering the composition, shape and strength of the synapse. These neuronal activity-dependent modifications are necessary for learning and memory and various behavioural responses, particularly during development. These features are altered in Intellectual Disability (ID) and Autism Spectrum Disorder (ASD), which affects ~1% of the world’s population. Heterozygous mutations in SYNGAP1 are one of the primary causes of Intellectual Disability (ID) and Autism Spectrum disorder (ASD). Thereby, aberrant maturation of dendritic spines leads to an anomalous Excitation-Inhibition (E/I) balance at the critical period of development. In part, such changes are linked with altered chloride co-transporters, NKCC1 and KCC2, in animal models of Fragile-X and Rett syndrome but unknown in Syngap1+/- during different developmental stages. We show that the expression, and function of chloride co-transporters NKCC1 and KCC2 at P14-15 heterozygous mice is altered. In addition, we discovered that administration of a novel GSK-3β inhibitor, 6BIO, during critical period of development and in the young adolescent rescued E/I balance and the deficits of synaptic transmission and behavioural performance like social novelty, anxiety and spatial memory in Syngap1+/- mice. Here, we demonstrated that the GABAergic circuit was disrupted during development and modulating this circuit restored cognitive, emotional, and social symptoms that result from hard-wired neuronal circuit damage during development by late pharmacological intervention in adulthood.


James’ career in neuroscience started as a Research Assistant in Prof Upinder Bhalla’s laboratory. He did his PhD in Prof. Randall’s lab, and Prof. Graham Collingridge as co-PI, for PhD in neuroscience at the University of Bristol, UK, where he worked on Group I mGluRs’ role in synaptic and intrinsic plasticity in the hippocampus. He moved to Scripps Research Institute, Florida, for a post-doc in Dr Gavin Rumbaugh’s laboratory, along with collaborators, did pioneering work in Syngap1+/- led to the understanding of the importance of the critical period of neuronal development and its link to Intellectual Disability (ID) and autism spectrum disorder (ASD). Since July 2013, his lab, using electrophysiology (mainly), 2-photon imaging, and molecular and biochemical techniques, continues to study how mutations in genes encoding proteins necessary for synaptic function cause ID and ASD using Syngap1+/- the Jawaharlal Nehru Centre for Advanced Scientific Research in Bengaluru, India. James’ work has been published in prestigious journals such as Science, Cell, and Nature neuroscience, apart from other major scientific journals.
Date: 24 November 2022, 16:00 (Thursday, 7th week, Michaelmas 2022)
Venue: Sherrington Building, off Parks Road OX1 3PT
Venue Details: Sherrington Room (second floor)
Speaker: Associate Professor James P Clement Chelliah, PhD (Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India)
Organising department: Department of Physiology, Anatomy and Genetics (DPAG)
Organiser: Professor Zoltan Molnar (DPAG, University of Oxford)
Organiser contact email address:
Host: Professor Zoltan Molnar (DPAG, University of Oxford)
Part of: Neuroscience Theme Guest Speakers (DPAG)
Booking required?: Not required
Audience: Members of the University only
Editor: Talitha Smith