James Mackay

James Mackay

 

Dr. James Mackay
Assistant Professor

Education:
BScPharm, University of Alberta, 2008
PhD, University of Alberta, 2016 

Teaching: Pharmacology 306, Pharmacology 425

Contact Information:
Office: 9-36 Medical Sciences Building
Email: jmackay@ualberta.ca 

Research: Altered brain activity as an early biomarker and drug-target in neurodegenerative diseases.

Research interests / laboratory techniques

The human brain is a marvel of biological complexity. 100 billion highly specialized electrical cells called neurons, communicate via hundreds of trillions of synaptic connections in ways not yet fully understood. This system constitutes a tangible basis for consciousness – a principal part of what makes you, you, and me, me. However, with age, the brain becomes increasingly vulnerable to neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s disease – amongst others), which perturb its intricate wiring and complex functioning. These debilitating conditions progressively diminish quality of life and productivity; and are alarmingly increasing in prevalence, secondary to aging population demographics and changing lifestyles/environmental factors.

I aim to better understand brain organization across multiple spatial scales in health and neurodegeneration: from the sub-neuronal (individual ion channels and organelles), to brain-wide neuronal networks. As a trained pharmacist and pharmacologists, I seek to identify novel drug targets and use available drug tools to explore key biological questions. Principal techniques used in my lab include in vivo imaging of brain activity (primarily using genetically encoded sensors – ex. GCaMP) and whole-cell patch clamp electrophysiology in acute brain slices - both leveraging rodent disease-models.

Key Projects:


Early biomarker identification:
In most neurodegenerative diseases, brain pathology begins decades prior to diagnosis and manifests first as altered neuronal activity/connectivity. This early-stage-disease is optimal for treatment interventions, as it generally precedes prominent irreversible neuronal death. However, current diagnostic strategies, which rely on observable symptoms, are ill-suited to identify patients until the brain’s considerable compensatory capacity is overwhelmed by substantial (irreversible) degeneration, much later in the disease course. Early objective biomarkers are thus needed; of which brain activity metrics arguably constitute the most direct. To this end, my lab images brain activity in mouse models of Huntington disease (HD) (the most common inherited neurodegenerative disease) and applies cutting-edge machine learning models to determine the earliest disease-course timepoints when we can reliably identify HD-mice from their WT littermates based on their brain activity. We then seek to determine underlying brain areas and activity patterns driving the above classification. This work informs analogous strategies that could be applied to human data, but also allows subsequent exploration of cellular mechanisms and causational analysis only possible in animal models, ultimately facilitating novel drug target discovery (see below).


Neuronal excitability in neurodegenerative disease:
Neurodegeneration is associated with complex, changes in neuronal excitability, these changes are incompletely understood and raise important questions. Is altered neuronal activity simply an outcome of impaired neuronal health, but otherwise causally unrelated to brain degeneration? Alternatively, does altered brain activity shape disease outcomes, either by driving pathology (through maladaptive synaptic plasticity for example) or mitigate damage and functional impairment through compensatory circuit changes. I hypothesize metabolic changes associated with aging alter neuronal firing (an exceptionally energetically demanding process) and in doing so, drive neurodegeneration. My lab is exploring the above questions with ex vivo patch clamp electrophysiology and in vivo wide-field cortical imaging, first in Huntington disease mice, with plans to expand to Alzheimer’s and Parkinson’s disease models. This dual experimental approach allows dissecting the determinants of brain activity at individual neuron and large scale neural network levels.

Select Publications

  1. Mackay JP, Smith-Dijak AI, Koch ET, Zhang P, Fung E, Nassrallah WB, Buran C, Schmidt M, Hayden MR and Raymond LA. Axonal ER Ca2+ release selectively enhances activity-independent glutamate release in a Huntington disease model (2023). J Neurosci. May17;43(20):3743-3763. https://doi.org/1523/JNEUROSCI.1593-22.2023.
  2. Cheng J, Koch ET, Ramandi D, Mackay JP, O’Leary TP, Rees-Jones W and Raymond LA. Synaptic modulation of glutamate in striatum of the YAC128 mouse model of Huntington disease (2025). Neurobiol Dis. Feb:205:106774. https://doi.org/10.1016/j.nbd.2024.106774.
  3. Nassrallah WB, Cheng J, Mackay JP, Hogg PW, Raymond LA. Mechanisms of Synapse-to-Nucleus Signalling in Striatal Neurons and Impairments in Huntington’s Disease (2024). J Neurochem. Sep;168(9):2671-2689. https://doi.org/10.1111/jnc.16132.
  4. Nassrallah WB, Ramandi D, Cheng J, Oh J, Mackay JP, Sepers MD, Lau D, Bading H and Raymond LA. Activin A targets extrasynaptic NMDA receptors to ameliorate neuronal and behavioral deficits in a mouse model of Huntington disease (2023). Neurobiol Dis. Nov 20:189:106360. https://doi.org/1016/j.nbd.2023.106360. 
  5. Wang Y, Ramandi D, Sepers MD, Mackay JP and Raymond LA. Age- and region-dependent cortical excitability in the zQ175 Huntington disease mouse model (2023). Hum Mol Genet. Nov 8:ddad191. https://doi.org/1093/hmg/ddad191
  6. Sepers MD, Mackay JP, Koch ET, Xiao D, Mohajerani MH, Chan AW, Smith-Dijak AI, Ramandi D, Murphy TH and Raymond LA. Altered cortical processing of sensory input in Huntington disease mouse models (2022). Neurobiol Dis. Jul:169:105740. https://doi.org/1016/j.nbd.2022.105740.
  7. Michaelson SD, Muller TM, Bompolaki M, Miranda Tapia A, Silveira Villarroel H, Mackay JP, Balogun PJ, Urban JH and Colmers WF. Long-Lived Organotypic Slice Culture Model of the Rat Basolateral Amygdala (2021). Curr Protoc. Oct;1(10):e267. https://doi.org/1002/cpz1.267.
  8. Michaelson SD, Miranda Tapia A, McKinty A, Silveira Villarroel H, Mackay JP, Urban JH and Colmers WF. Contribution of NPY Y5 receptors to the reversible structural remodeling of basolateral amygdala dendrites in male rats associated with NPY-mediated stress resilience (2020). J Neurosci. 40:3231-3249. https://doi.org/1523/JNEUROSCI.2621-19.2020.
  9. Mackay JP, Bompolaki M, DeJoseph MR, Michaelson SD, Urban JH and Colmers WF. NPY2 receptors reduce tonic action potential-independent GABAB currents in the basolateral amygdala (2019). J Neurosci. 39:4909-4930. https://doi.org/1523/JNEUROSCI.2226-18.2019.
  10. Schmidt M, Buran C, Mackay JP, Cheung D, Dal Cengio L, Raymond LA, Hayden MR. Altering cortical input unmasks synaptic phenotypes in the YAC128 cortical-striatal co-culture model of Huntington’s disease (2018). BMC Biol. Jun 27;16(1):58. https://doi.org/1186/s12915-018-0526-3.
  11. Silveira Villarroel H, Bompolaki M, Mackay JP, Miranda Tapia A, Michaelson SD, Leitermann RJ, Marr RA, Urban JH and Colmers WF. NPY induces stress resilience via downregulation of Ih in principal neurons of rat basolateral amygdala (2018). J Neurosci. May 9;38(19):4505-4520. https://doi.org/1523/JNEUROSCI.3528-17.2018.
  12. Mackay JP, Nassrallah WB and Raymond LA. Cause or compensation? – altered neuronal Ca2+ handling in Huntington’s disease (2018). CNS Neurosci Ther. Apr;24(4):301-310. https://doi.org/1111/cns.12817.
  13. Zangrandi L, Burtscher J, Mackay JP, Colmers WF, Schwarzer C. The G-Protein Biased Partial κ Opioid Receptor Agonist 6'-GNTI Blocks Hippocampal Paroxysmal Discharges Without Inducing Aversion (2016). Br J Pharmacol 173:1756–1767. https://doi.org/10.1111/bph.13474.
  14. Ferdaoussi M,  Dai XQ, Jensen MV, Wang R, Peterson BS, Huang C, Ilkayeva O, Smith N, Miller N, Hajmrle C, Spigelman AF, Wright RC, Plummer G, Suzuki K, Mackay JP, van de Bunt M, Gloyn AL, Ryan TE, Norquay LD, Brosnan MJ, Trimmer JK, Rolph TP, Kibbey RG, Manning Fox JE,Colmers WF, Shirihai OS, Neufer PD, Yeh ETH, Newgard CB, MacDonald PE. Isocitrate-to-SENP1 Signaling Amplifies Insulin Secretion and Rescues Dysfunctional β Cells (2015). J Clin Invest 125:3847–3860. https://doi.org/10.1172/jci82498.
  15. Giesbrecht CJ, Mackay JP, Silveira HB, Urban JH, Colmers WF. Countervailing Modulation of Ih by Neuropeptide Y and Corticotrophin-Releasing Factor in Basolateral Amygdala as a Possible Mechanism for Their Effects on Stress-Related Behaviors (2010). J Neurosci. Dec 15;30(50):16970-82. https://doi.org/10.1523/jneurosci.2306-10.2010.