I completed my BSc in Psychology and Health Studies (2010) at the University of Toronto. From 2011 -2013, I conducted my MSc under the supervision of Dr. Alastair Ferguson at Queen’s University, where I characterized the effects of hydrogen sulfide on the paraventricular nucleus (PVN). Shortly after, I returned to the University of Toronto for my PhD (2014 – 2018) where, under the supervision of Dr. Melanie Woodin, I studied the role of cortical interneurons in amyotrophic lateral sclerosis (ALS). I joined the YDK Lab in 2018 as a post doctoral fellow with the continued focus of better understanding the role that the inhibitory system plays in ALS.
Examining the role of KCC2 in ALS
ALS is a rapidly progressive neurodegenerative disorder that preferentially affects both the upper and lower motor neurons in the CNS. Hyperexcitability in the spinal cord is a feature of ALS during the pre-symptomatic phase of the disorder. While the substrates of this hyperexcitability can be many, recent studies have identified a particularly interesting new target: the CNS-specific potassium-chloride cotransporter, KCC2. Patients with the sporadic form of ALS have shown a downregulation of the gene SCL12A5, which encodes for KCC2. KCC2 is responsible for maintaining a low concentration of chloride in neurons, which is crucial to maintain the strength of inhibition. Previous published work from the De Koninck lab has identified compounds to enhance KCC2 activity. These compounds, namely, CLP257 and CLP290, have shown efficacy in restoring KCC2 hypofunction in pathological conditions, with minimal side effect profiles. That is, it was possible to not only prevent the development of hyperexcitability, but also to reverse it once established. Thus, the main objective of this present project is to directly test whether restoring KCC2 with KCC2 activators, either at the cortical or spinal level or both can prevent neurodegeneration and motor deficits associated with ALS. In addition, I am interested in testing whether KCC2 can be used as a reliable biomarker for some forms of ALS and whether the rescue of neurodegeneration and ALS associated motor symptoms can be achieved when targeted symptomatically. I was awarded a post-doctoral fellowship for this project from ALS Canada and Brain Canada in partnership with La Fondation Vincent Bourque ( https://www.als.ca/projects-funded-2018/ ).
Developing new behavioural tests to uncover subtle changes in upper and lower motor neuron health in ALS
ALS is a devastating disorder that belongs to a broad group of disorders known as MNDs. This fatal disease is characterized by catastrophic muscle weakness and atrophy that eventually spreads across the body as it progresses into later stages. There are three main presentations of ALS: bulbar-onset ALS, limb-onset ALS and pure UMN or LMN ALS. Typically, UMN disturbance involving the limbs leads to spasticity, weakness, and brisk deep tendon reflexes and LMN limb features include fasciculations, wasting, and weakness. Bulbar onset results in slow, labored, and distorted speech, often with a nasal quality, tongue wasting, weakness, and fasciculations, accompanied by flaccid dysarthria and later dysphagia. It is crucial to understand the specificities of the different presentations of ALS as it has important implications for patients, particularly concerning prognosis and survival. Understanding these differences also becomes important when developing pre-clinical treatment options in rodent models of ALS. Thus, I am currently developing a novel motor performance test with the aim of differentiating the subtle changes in performance that follow as a result of the loss or either UMNs or LMNs.
Amyotrophic lateral sclerosis, cortical interneurons, motor neurons, motor cortex, spinal cord, synaptic transmission, E:I balance, network hyperexcitability, motor physiology, chloride homeostasis, K+/Cl- Cotransporters (NKCC1/KCC2) and KCC2 enhancers
Electrophysiology, In vivo Photometry, immunohisto- and cytochemistry, confocal and electron microscopy, fluorescence spectroscopy, biochemical assays, chemogenetics, behavioral measurements, and neuropharmacology
Khademullah CS, Aqrabawi AJ, Place KM, Dargaei Z, Liang X, Pressey JC, Bedard S, Yang J, Garand D, Keramidis I, Gasecka A, Côté D, De Koninck Y, Keith J, Zinman L, Robertson J, Kim JC, Woodin MA. (2020). Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis. Brain. doi: 10.1093/brain/awaa034. PMID: 32203578.
Dargaei Z, Bang JY, Mahadevan V, Khademullah CS, Bedard S, Parfitt GM, Kim JC, Woodin MA. (2018). Restoring GABAergic inhibition rescues memory deficits in a Huntington’s disease mouse model. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.1716871115. Epub 2018 Jan 30. PMID: 29382760; PMCID: PMC5816181.
Mahadevan V, Khademullah CS, Dargaei Z, Chevrier J, Uvarov P, Kwan J, Bagshaw RD, Pawson T, Emili A, De Koninck Y, Anggono V, Airaksinen M, Woodin MA. (2017). Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition. Elife. doi: 10.7554/eLife.28270. PMID: 29028184; PMCID: PMC5640428.
Pressey JC, Mahadevan V, Khademullah CS, Dargaei Z, Chevrier J., Chauhan AK, Meas SJ, Uvarov P, Airaksinen MS, Woodin MA., (2017). Kainate Receptor Subunit Promotes the Recycling of the Neuron-Specific K+-Cl Cotransporter KCC2 in Hippocampal Neurons. Journal of Biological Chemistry. doi: 10.1074/jbc.M116.767236. Epub 2017 Feb 24. PMID: 28235805; PMCID: PMC5391750.
Aqrabawi AJ, Browne CJ, Dargaei Z, Garand D, Khademullah CS, Woodin MA, Kim JC. (2016). Top-down modulation of olfactory-guided behaviours by the anterior olfactory nucleus pars medialis and ventral hippocampus. Nature Communications. doi: 10.1038/ncomms13721. PMID: 28004701; PMCID: PMC5192165.
Khademullah CS & Ferguson AV. (2013). Depolarizing actions of hydrogen sulfide on hypothalamic paraventricular nucleus neurons. PLoS ONE. doi: 10.1371/journal.pone.0064495. PMID: 23691233; PMCID: PMC3656899.
Thiele SL, Warre R, Khademullah CS, Farhana N, Lo C, Lam D, Talwar S, Johnston TH, Brotchie JM, Nash JE. (2011). Generation of a model of L-DOPA-induced dyskinesia in two different mouse strains. Journal of Neuroscience Methods. doi; 10.1016/j.jneumeth.2011.02.012. PMID: 21352853.
Warre R, Johnston T, Wang S, Khademullah CS, Talwar S, Perera G, Thiele S, Reyes G., Sun XS, Brotchie J, Nash J. (2010). Altered function of glutamatergic cortico-striatal synapses causes output pathway abnormalities in a chronic model of parkinsonism. Neurobiology of Disease. Doi; 10.1016/j.nbd.2010.10.013. . PMID: 20971190.