Foundational Science

• Bernardo AM, Marcotte M, Wong K, Sharmin D, Pandey KP, Cook JM, Sibille EL, Prevot TD. Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition mouse model of Alzheimer’s disease pathology. Neurobiology of Aging. 2025 March; 147:(49-59). Epub https://doi.org/10.1016/j.neurobiolaging.2024.12.001.
  This study provided preclinical proof of concept data demonstrating the symptomatic and disease-modifying potential of DPX-101 (GL-II-73) for the treatment of cognitive deficits in Alzheimer’s disease. Small molecule DPX-101 improved working memory deficits and prevented neuronal shrinkage and spine loss in early and late stages of β-amyloid deposition in the 5xFAD mouse model of Alzheimer’s disease-related β-amyloid pathology.

• Guet-McCreight A, Chameh HM, Mazza F, Prevot TD, Valiante TA, Sibille E, Hay E. In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression. Commun Biol. 2024 Feb 23;7(1):225. doi: 10.1038/s42003-024-05907-1. PMID: 38396202
  In this computational modeling study, we identified simulated EEG biomarker candidates, which could be used to facilitate α5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.

• Bernardo AM, Marcotte M, Wong K, Sharmin D, Pandey KP, Cook JM, Sibille E, Prevot TD. Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition model of Alzheimer’s disease pathology. Neurobiology of Aging. 2022.
  In this rodent study, we show that acute or chronic administration of α5-PAM can reverse the cognitive deficits induced by the accumulation of amyloid plaques in a mouse model of Alzheimer’s pathology. We also show that chronic administration of α5-PAMblocks or reverse the loss of spines in this model. Both effects are observed in early and late stages of AD pathologies, independently form amyloid deposition.

• Luscher B, Maguire JL, Rudolph U, Sibille E. GABAA receptors as targets for treating affective and cognitive symptoms of depression. Trends Pharmacol Sci. 2023 Sep;44(9):586-600. doi: 10.1016/j.tips.2023.06.009. Epub 2023 Aug 3. PMID: 37543478
  This review summarizes the role of GABA in depression and the putative therapeutic effects of allopregnanolone and α5-PAM for depressive and cognitive symptoms, respectively.

• McCoy AM, Prevot TD, Mian MY, Cook JM, Frazer A, Sibille EL, Carreno FR, Lodge DJ. Positive Allosteric Modulation of α5-GABAA Receptors Reverses Stress-Induced Alterations in Dopamine System Function and Prepulse Inhibition of Startle. Int J Neuropsychopharmacol. 2022 Aug 16;25(8):688-698. doi: 10.1093/ijnp/pyac035. PMID: 35732272
  In this rodent study, we provide a proof-of-concept for the use of α5-PAM in reversing the hyperdopaminergic activity observed in models of PTSD.

• Bernardo A, Lee P, Marcotte M, Mian MY, Rezvanian S, Sharmin D, Kovačević A, Savić MM, Cook JM, Sibille E, Prevot TD. Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress. Neuropsychopharmacology. 2022 Aug;47(9):1608-1619. doi: 10.1038/s41386-022-01360-y. Epub 2022 Jun 14. PMID: 35701547
  In this rodent study, we show that chronic administration of α5-PAM can reverse the atrophy of brain cells that occur during chronic stress, in addition to reversing cognitive deficits.

• Tomoda T, Sumitomo A, Newton D, Sibille E. Molecular origin of somatostatin-positive neuron vulnerability. Mol Psychiatry. 2022 Apr;27(4):2304-2314. doi: 10.1038/s41380-022-01463-4. Epub 2022 Feb 10. PMID: 35145229
  In this rodent study, we describe the molecular mechanisms that underlie the biological vulnerability of SST-neuron. There results provide a rationale for the finding of decrease SST neuron structure and function across brain disorders, and suggest novel targets to restore SST cell function.

• Yao HK, Guet-McCreight A, Mazza F, Chameh HM, Prevot TD, Griffiths J, Tripathy ST, Valiante TA, Sibille E, Hay E. Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits. Cell Reports. 2022 Jan 11;38(2):110232. doi: 10.1016/j.celrep.2021.110232. PMID: 35021088
  In this novel computational model of human cortical microcircuits, we show that decreased function of Sst cells leads to alter cognitive processes, including increased noise during information processing and increased false and failed detection of stimuli.

• Fee C, Prevot TD, Misquitta K, Knutson DE, Li G, Mondal P, Cook JM, Banasr M, Sibille E. Behavioral deficits induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation. Int J Neuropsychopharmacol. 2021 Jul 14;24(6):505-518. doi: 10.1093/ijnp/pyab002. PMID: 33438026
  In the report we first used a pharmacogenetic approach to reduce the function of SST cell across the brain (mimicking human fndings) and show that it is sufficient to induce mood symptoms and cognitive deficits in mice. We then show that we can rescue these deficits using an α5-PAM, together confirming our central hypotheses of disease mechanism and of therapeutic approach.

• Prevot TD, Sumitomo A, Tomoda T, Knutson DE, Li G, Mondal P, Banasr M, Cook J, and Sibille E. Reversal of age-related neuronal atrophy by α5-GABAA receptor positive allosteric modulation. Cerebral Cortex. 2021 Jan 5;31(2):1395-1408. doi: 10.1093/cercor/bhaa310. PMID: 33068001
  In this rodent study, we show that chronic administration of α5-PAM can reverse the atrophy of brain cells that occur during aging, in addition to reversing cognitive deficits.

• Prevot T, Sibille E. Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders. Mol Psychiatry. 2020 Apr 28. doi: 10.1038/s41380-020-0727-3. Epub ahead of print. PMID: 32346158.
  In this extensive review, we summarize the evidence for cognitive deficits in depression, link them to GABAergic deficits, and highlight the role of augmenting α5-GABAA-R either α5-PAM as a novel therapeutic approach for cognitive dysfunction in depression and n potentially across other brain disorders.

• Newton DF, Fee C, Nikolova YS, Sibille E. Altered GABAergic function, cortical microcircuitry, and information processing in depression. In Neurobiology of Depression, Academic Press, 2019: 315-329.
  This book chapter is a thorough review on altered GABAergic function, cortical microcircuitry, and information processing in depression.

• Hu X, Rocco BR, Fee C, Sibille E. Cell Type-Specific Gene Expression of Alpha 5 Subunit-Containing Gamma-Aminobutyric Acid Subtype A Receptors in Human and Mouse Frontal Cortex. Mol Neuropsychiatry. 2019 Feb;4(4):204-215. doi: 10.1159/000495840. Epub 2019 Jan 23. PMID: 30815456; PMCID: PMC6388437.
  In this anatomical study, we established the exact cellular expression of the 5-GABAA-R in the human and mouse brain, showing almost identical profiles across species.