@article{pmid41962851,

title = {Excessive inhibition in the medial prefrontal cortex contributes to cognitive susceptibility in aging},

author = {Iason Keramidis and Patrick Desrosiers and Andrée-Anne Verreault and Romain Sansonetti and Reza Hazrati and Antoine G Godin and Yves De Koninck},

doi = {10.1016/j.nbd.2026.107385},

issn = {1095-953X},

year  = {2026},

date = {2026-04-01},

journal = {Neurobiol Dis},

volume = {224},

pages = {107385},

abstract = {Aging is the most impactful risk factor for cognitive decline. The prefrontal cortex (PFC), a brain region essential for higher-order cognition, undergoes age-related synaptic alterations which are postulated to yield an excitation/inhibition imbalance within the PFC. Here, we assessed cognitive performance in young and aged mice using a battery of behavioral tests linked to PFC function. Behavioral variability within the aged cohort suggested structured heterogeneity in cognitive performance. Using a data-driven analytical framework integrating behavioral dimensionality reduction, consensus clustering, and spectral embedding we achieved robust and stable behavioral subgroup separation within the aged population. This approach revealed a subset of "cognitively susceptible" aged mice with pronounced memory and novelty-directed exploration deficits, distinct from both "resilient" aged mice and young controls. Unlike resilient aged mice, susceptible mice showed intact social preference. Susceptible aged mice exhibited elevated levels of the inhibitory synaptic proteins Gephyrin and VGAT in the PFC, a pattern absent in resilient aged mice. Notably, the increase in Gephyrin was accounted for by a higher density of inhibitory synapses, indicating a structural shift toward inhibition. Consistent with this mechanism, optogenetically enhancing inhibition in the PFC of young mice was sufficient to recapitulate the memory and novelty-exploration deficits observed in susceptible aged mice. Altogether, these findings implicate excessive prefrontal inhibition as a mechanistic substrate contributing to cognitive susceptibility in unsuccessful aging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40667986,

title = {Decreased KCC2 expression in the human spinal dorsal horn associated with chronic pain and long-term opioid use},

author = {Olivia C Davis and Samuel Ferland and Louis-Etienne Lorenzo and Clare Murray-Lawson and Stephanie Shiers and Muhammad Saad Yousuf and Annemarie Dedek and Eve C Tsai and Erin Vines and Peter Horton and Anna Cervantes and Tariq Khan and Geoffrey Funk and Gregory Dussor and Antoine G Godin and Francesco Ferrini and Yves De Koninck and Michael E Hildebrand and Theodore J Price},

doi = {10.1097/j.pain.0000000000003700},

issn = {1872-6623},

year  = {2025},

date = {2025-11-01},

journal = {Pain},

volume = {166},

number = {11},

pages = {e665--e673},

abstract = {Loss of GABAergic and glycinergic inhibitory efficacy in the spinal dorsal horn is associated with neuropathic pain and opioid-induced hyperalgesia in rodent models. Downregulation of the KCC2 chloride extrusion transporter is a key mechanism underlying this decreased inhibitory efficacy, but to-date there is no evidence supporting or opposing this hypothesis in humans. Here, we demonstrate that KCC2 expression is decreased in superficial dorsal horn neurons of organ donors who died with a documented history of pain, or of long-term opioid use. We show profoundly decreased KCC2 dorsal horn membrane expression in a primary cohort associated with either chronic pain or opioid use, and in a replication cohort of mixed chronic pain and opioid use history. These results show that decreased dorsal horn inhibitory efficacy likely promotes chronic pain in humans and support the development of therapeutics augmenting KCC2 function as a treatment for chronic pain and opioid use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40309929,

title = {Focus on numbers - characterizing protein accumulation at DNA double-strand breaks},

author = {Graziana Modica and Joannie Roy and Antoine G Godin and Hugo Wurtele and Santiago Costantino},

doi = {10.1242/jcs.263483},

issn = {1477-9137},

year  = {2025},

date = {2025-06-01},

journal = {J Cell Sci},

volume = {138},

number = {11},

abstract = {Unrepaired DNA double-strand breaks can lead to cell death or genomic rearrangements. The DNA damage response (DDR) is a complex signaling cascade in which a plethora of factors act to finely tune repair pathway choice. Several DDR proteins have been shown to accumulate at sites of DNA lesions in characteristic dot-like structures known as DNA repair foci. Changes in foci brightness, commonly expressed in arbitrary intensity units, are often used as readout for DNA repair dynamics. However, due in part to technical challenges, the stoichiometry, absolute number of proteins recruited to DDR foci, and their impact on the resolution of the break remain incompletely characterized. Here, we combine spatial intensity distribution analysis (SpIDA) and a custom foci detection algorithm into an easy-to-use pipeline that, starting from confocal images, allows quantitative description of protein accumulation in DNA repair foci. Moreover, by quantifying foci based on their molecular count, SpIDA overcomes the limitations of ambiguous intensity units, enabling stoichiometric quantification between repair factors and providing a unifying means for experimental comparisons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39625537,

title = {Mathematical properties of pump-leak-cotransport models},

author = {Vincent Ouellet and Nicolas Doyon and Antoine G Godin and Pierre Marquet},

doi = {10.1007/s00285-024-02163-z},

issn = {1432-1416},

year  = {2024},

date = {2024-12-01},

journal = {J Math Biol},

volume = {90},

number = {1},

pages = {2},

abstract = {Models of ordinary differential equations are often used to describe the electrical, ionic and volumetric responses of cells to external stimuli. Although these cellular models are often solved numerically, rigorous evidence regarding their steady state solutions is scarce. In this work, we provide a formalism defining the conditions ensuring the existence and uniqueness of a steady-state solution in a large class of models including leak channels, a pump and cotransporters. Our work generalizes previous results and provides explicit conditions that a model must satisfy to guarantee the existence and uniqueness of a steady state.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37551444,

title = {Restoring neuronal chloride extrusion reverses cognitive decline linked to Alzheimer's disease mutations},

author = {Iason Keramidis and Brendan B McAllister and Julien Bourbonnais and Feng Wang and Dominique Isabel and Edris Rezaei and Romain Sansonetti and Phil Degagne and Justin P Hamel and Mojtaba Nazari and Samsoon Inayat and Jordan C Dudley and Annie Barbeau and Lionel Froux and Marie-Eve Paquet and Antoine G Godin and Majid H Mohajerani and Yves De Koninck},

doi = {10.1093/brain/awad250},

issn = {1460-2156},

year  = {2023},

date = {2023-12-01},

journal = {Brain},

volume = {146},

number = {12},

pages = {4903--4915},

abstract = {Disinhibition during early stages of Alzheimer's disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer's disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer's disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer's disease-related cognitive decline; they confirm target engagement, where the therapeutic intervention takes place, and its effectiveness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37792939,

title = {Enhanced harm detection following maternal separation: Transgenerational transmission and reversibility by inhaled amiloride},

author = {Marco Battaglia and Orlane Rossignol and Louis-Etienne Lorenzo and Jasmin Deguire and Antoine G Godin and Francesca R D'Amato and Yves De Koninck},

doi = {10.1126/sciadv.adi8750},

issn = {2375-2548},

year  = {2023},

date = {2023-10-01},

journal = {Sci Adv},

volume = {9},

number = {40},

pages = {eadi8750},

abstract = {Early-life adversities are associated with altered defensive responses. Here, we demonstrate that the repeated cross-fostering (RCF) paradigm of early maternal separation is associated with enhancements of distinct homeostatic reactions: hyperventilation in response to hypercapnia and nociceptive sensitivity, among the first generation of RCF-exposed animals, as well as among two successive generations of their normally reared offspring, through matrilineal transmission. Parallel enhancements of acid-sensing ion channel 1 (ASIC1), ASIC2, and ASIC3 messenger RNA transcripts were detected transgenerationally in central neurons, in the medulla oblongata, and in periaqueductal gray matter of RCF-lineage animals. A single, nebulized dose of the ASIC-antagonist amiloride renormalized respiratory and nociceptive responsiveness across the entire RCF lineage. These findings reveal how, following an early-life adversity, a biological memory reducible to a molecular sensor unfolds, shaping adaptation mechanisms over three generations. Our findings are entwined with multiple correlates of human anxiety and pain conditions and suggest nebulized amiloride as a therapeutic avenue.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37817802,

title = {A robust and reliable methodology to perform GECI-based multi-time point neuronal calcium imaging within mixed cultures of human iPSC-derived cortical neurons},

author = {Niraj Patel and Vincent Ouellet and François Paquet-Mercier and Nizar Chetoui and Erik Bélanger and Marie-Eve Paquet and Antoine G Godin and Pierre Marquet},

doi = {10.3389/fnins.2023.1247397},

issn = {1662-4548},

year  = {2023},

date = {2023-01-01},

journal = {Front Neurosci},

volume = {17},

pages = {1247397},

abstract = {INTRODUCTION: Human induced pluripotent stem cells (iPSCs), with their ability to generate human neural cells (astrocytes and neurons) from patients, hold great promise for understanding the pathophysiology of major neuropsychiatric diseases such as schizophrenia and bipolar disorders, which includes alterations in cerebral development. Indeed, the  neurodifferentiation of iPSCs, while recapitulating certain major stages of neurodevelopment , makes it possible to obtain networks of living human neurons. The culture model presented is particularly attractive within this framework since it involves iPSC-derived neural cells, which more specifically differentiate into cortical neurons of diverse types (in particular glutamatergic and GABAergic) and astrocytes. However, these  neuronal networks, which may be heterogeneous in their degree of differentiation, remain challenging to bring to an appropriate level of maturation. It is therefore necessary to develop tools capable of analyzing a large number of cells to assess this maturation process. Calcium (Ca) imaging, which has been extensively developed, undoubtedly offers an incredibly good approach, particularly in its versions using genetically encoded calcium indicators. However, in the context of these iPSC-derived neural cell cultures, there is a lack of studies that propose Ca imaging methods that can finely characterize the evolution of neuronal maturation during the neurodifferentiation process.nnMETHODS: In this study, we propose a robust and reliable method for specifically measuring neuronal activity at two different time points of the neurodifferentiation process in such human neural cultures. To this end, we have developed a specific Ca signal analysis procedure and tested a series of different AAV serotypes to obtain expression levels of GCaMP6f under the control of the neuron-specific human synapsin1 (hSyn) promoter.nnRESULTS: The retro serotype has been found to be the most efficient in driving the expression of the GCaMP6f and is compatible with multi-time point neuronal Ca imaging in our human iPSC-derived neural cultures. An AAV2/retro carrying GCaMP6f under the hSyn promoter (AAV2/retro-hSyn-GCaMP6f) is an efficient vector that we have identified. To establish the method, calcium measurements were carried out at two time points in the neurodifferentiation process with both hSyn and CAG promoters, the latter being known to provide high transient gene expression across various cell types.nnDISCUSSION: Our results stress that this methodology involving AAV2/retro-hSyn-GCaMP6f is suitable for specifically measuring neuronal calcium activities over multiple time points and is compatible with the neurodifferentiation process in our mixed human neural cultures.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35895817,

title = {Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain},

author = {Franck Aby and Louis-Etienne Lorenzo and Zoé Grivet and Rabia Bouali-Benazzouz and Hugo Martin and Stéphane Valerio and Sara Whitestone and Dominique Isabel and Walid Idi and Otmane Bouchatta and Philippe De Deurwaerdere and Antoine G Godin and Cyril Herry and Xavier Fioramonti and Marc Landry and Yves De Koninck and Pascal Fossat},

doi = {10.1126/sciadv.abo0689},

issn = {2375-2548},

year  = {2022},

date = {2022-07-01},

journal = {Sci Adv},

volume = {8},

number = {30},

pages = {eabo0689},

abstract = {Descending control from the brain to the spinal cord shapes our pain experience, ranging from powerful analgesia to extreme sensitivity. Increasing evidence from both preclinical and clinical studies points to an imbalance toward descending facilitation as a substrate of pathological pain, but the underlying mechanisms remain unknown. We used an optogenetic approach to manipulate serotonin (5-HT) neurons of the nucleus raphe magnus that project to the dorsal horn of the spinal cord. We found that 5-HT neurons exert an analgesic action in naïve mice that becomes proalgesic in an experimental model of neuropathic pain. We show that spinal KCC2 hypofunction turns this descending inhibitory control into paradoxical facilitation; KCC2 enhancers restored 5-HT-mediated descending inhibition and analgesia. Last, combining selective serotonin reuptake inhibitors (SSRIs) with a KCC2 enhancer yields effective analgesia against nerve injury-induced pain hypersensitivity. This uncovers a previously unidentified therapeutic path for SSRIs against neuropathic pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35323848,

title = {Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain},

author = {Annemarie Dedek and Jian Xu and Louis-Étienne Lorenzo and Antoine G Godin and Chaya M Kandegedara and Geneviève Glavina and Jeffrey A Landrigan and Paul J Lombroso and Yves De Koninck and Eve C Tsai and Michael E Hildebrand},

doi = {10.1093/brain/awab408},

issn = {1460-2156},

year  = {2022},

date = {2022-04-01},

journal = {Brain},

volume = {145},

number = {3},

pages = {1124--1138},

abstract = {The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund's adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36249484,

title = {Computational modeling of trans-synaptic nanocolumns, a modulator of synaptic transmission},

author = {Xiaoting Li and Gabriel Hémond and Antoine G Godin and Nicolas Doyon},

doi = {10.3389/fncom.2022.969119},

issn = {1662-5188},

year  = {2022},

date = {2022-01-01},

journal = {Front Comput Neurosci},

volume = {16},

pages = {969119},

abstract = {Understanding synaptic transmission is of crucial importance in neuroscience. The spatial organization of receptors, vesicle release properties and neurotransmitter molecule diffusion can strongly influence features of synaptic currents. Newly discovered structures coined trans-synaptic nanocolumns were shown to align presynaptic vesicles release sites and postsynaptic receptors. However, how these structures, spanning a few tens of nanometers, shape synaptic signaling remains little understood. Given the difficulty to probe submicroscopic structures experimentally, computer modeling is a useful approach to investigate the possible functional impacts and role of nanocolumns. In our  model, as has been experimentally observed, a nanocolumn is characterized by a tight distribution of postsynaptic receptors aligned with the presynaptic vesicle release site and by the presence of trans-synaptic molecules which can modulate neurotransmitter molecule diffusion. In this work, we found that nanocolumns can play an important role in reinforcing synaptic current mostly when the presynaptic vesicle contains a small number of neurotransmitter molecules. Our work proposes a new methodology to investigate  how the existence of trans-synaptic nanocolumns, the nanometric organization of the synapse and the lateral diffusion of receptors shape the features of the synaptic current such as its amplitude and kinetics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}