Disease Neurobiology

Dysfunction of neurotransmission precipitates in a wide range of neuropsychiatric and neurodevelopmental disorders.

In the post genomics era of personalised medicine, there is paucity of mechanistic understanding of genotype-phenotype relationships of disease variants from biophysical to behavioural levels. In addition, targeting precise intervention in neurological disorders requires the study and understanding of the mechanistic origins of these disorders.

Using a range of interdisciplinary approaches involving murine and human cells, I have over a decade of experience of probing receptor and ion channel mechanisms in neurological disorders.

In the pages below, examples of some of our work aimed at addressing the neurobiology of diseases can be found.

Developmental and Epileptic Encephalopathy: spontaneously active GABA_A receptors can counterintuitively underlie seizures

Contrary to established roles of GABA_Areceptors in seizures, here we show that individuals with developmental and epileptic encephalopathy harbour spontaneously active GABA_A receptor variants. These result in high levels of tonic inhibition and defects in dendritic spine plasticity that can be reversed by an inhibitory neurosteriod

Developmental and Epileptic Encephalopathy: reduced signaling efficacy and differential assembly of a GABA_A receptor variant

In line with a traditional view of GABA_A receptors in seizures, we report that a variant reduces efficacy of inhibition due to reduced cell surface expression. Unusually, variant receptors differentially assemble with other subunits and we provide evidence of tri-heteromeric receptors in the context of neurodevelopmental diseases

Developmental and Epileptic Encephalopathy: presynaptic hyperexcitability underlies GABA_B receptor variant seizures

In GABA_B receptor variant genetic epilepsies, we demonstrate that GABA_B receptor positive allosteric modulation reduces presynaptic hyperexcitability underlying variant expression in neurons highlighting the therapeutic potential of this class of agents for the treatment of debilitating genetic seizures

Rett syndrome: hyperactive GABA_B receptors in atypical Rett

Recently, two GABA_B receptor variants have been identified in several individuals with atypical Rett syndrome. In ongoing work as part of an International Rett Syndrome Foundation Fellowship, we have characterised these variants

Down syndrome: hippocampal circuit specific overhibition underlies cognitive deficits

A global elevation of GABAergic inhibition has been postulated to underlie behavioural deficits in Down syndrome. Contrary to this, our results using refined models show that the overinhibtion is more subtle affecting only specific brain circuits

Intellectual disability: Shroom4 variants impair GABA_B receptor function

In collaboration with Dr Jonathan Zapata and Professor Maria Passaffaro (CNR, Milan, Italy) we show that variants of the protein Shroom4 impair GABA_B receptor function