Diane C. Lagace

University of Ottawa

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Co-Authors

Amelia J. Eisch

University of Pennsylvania

Ruth S. Slack

University of Ottawa

Jagroop Dhaliwal

Hospital for Sick Children

David S. Park

California Northstate University

Alena Kalinina

University of Ottawa

Yingben Xue

University of Ottawa

Eric J. Nestler

Icahn School of Medicine at Mount Sinai

Vaishnav Krishnan

Baylor College of Medicine

Jean-Claude Béı̈que

University of Ottawa

Timal S. Kannangara

University of Victoria

Cooperative Institutions

Inserm

166

University of Ottawa

160

Centre National de la Recherche Scientifique

146

Harvard University

140

University of Michigan–Ann Arbor

136

The University of Texas Southwestern Medical Center

100

Chinese Academy of Sciences

National Institutes of Health

Ottawa Hospital

Istituti di Ricovero e Cura a Carattere Scientifico

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Conditional Disruption of Calpain in the CNS Alters Dendrite Morphology, Impairs LTP, and Promotes Neuronal Survival following Injury

Journal of Neuroscience (2013)

Mandana Amini Chun-Lei Ma Rasoul Farazifard Guoqi Zhu Yi Zhang

Ubiquitous classical (typical) calpains, calpain-1 and calpain-2, are Ca +2 -dependent cysteine proteases, which have been associated with numerous physiological and pathological cellular functions. However, a clear understanding of the role of calpains in the CNS has been hampered by the lack of appropriate deletion paradigms in the brain. In this study, we describe a unique model of conditional deletion of both calpain-1 and calpain-2 activities in mouse brain, which more definitively assesses the role of these ubiquitous proteases in brain development/function and pathology. Surprisingly, we show that these calpains are not critical for gross CNS development. However, calpain-1/calpain-2 loss leads to reduced dendritic branching complexity and spine density deficits associated with major deterioration in hippocampal long-term potentiation and spatial memory. Moreover, calpain-1/calpain-2-deficient neurons were significantly resistant to injury induced by excitotoxic stress or mitochondrial toxicity. Examination of downstream target showed that the conversion of the Cdk5 activator, p35, to pathogenic p25 form, occurred only in the presence of calpain and that it played a major role in calpain-mediated neuronal death. These findings unequivocally establish two central roles of calpain-1/calpain-2 in CNS function in plasticity and neuronal death.

Calpastatin

Dendrite (mathematics)

10.1523/jneurosci.4247-12.2013

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Citations (93)

Inhibition of inflammation by minocycline improves heart failure and depression-like behaviour in rats after myocardial infarction

PLoS ONE (2019)

Hongwei Wang Monir Ahmad Rami Jadayel Fatimah Najjar Diane C. Lagace

Patients with heart failure have an increased incidence of depression. Central and peripheral inflammation play a major role in the pathophysiology of both heart failure and depression.

Minocycline

Depression

10.1371/journal.pone.0217437

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Citations (35)

Increasing PC survival is not sufficient to enhance spatial learning and memory in naïve conditions

Marc A. Vani Maheen Ceizar M. Hasu Diane C. Lagace

Source

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Citations (0)

An antibody for analysis of autophagy induction

Nature Methods (2019)

Wensheng Tian Reham M. Alsaadi Zhihao Guo Alena Kalinina Micaël Carrier

ATG16L1

ULK1

BAG3

Autophagy-related protein 13

10.1038/s41592-019-0661-y

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Citations (53)

Hippocampal Neurogenesis: A Matter of Survival

American Journal of Psychiatry (2007)

Diane C. Lagace

10.1176/appi.ajp.164.2.205

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Citations (2)

A longitudinal study of stress‐induced hippocampal volume changes in mice that are susceptible or resilient to chronic social defeat

Hippocampus (2014)

Yiu Chung Tse Ixchel Montoya Alice S. Wong Axel Mathieu Jennifer I. Lissemore

Hippocampal shrinkage is a commonly found neuroanatomical change in stress-related mood disorders such as depression and post-traumatic stress disorders (PTSD). Since the onset and severity of these disorders have been found to be closely related to stressful life events, and as stress alone has been shown to reduce hippocampal volume in animal studies, vulnerability to mood disorders may be related to a susceptibility to stress-induced hippocampal shrinkage. However, a smaller hippocampal volume before stress exposure has also been suggested to confer vulnerability of stressed individuals to PTSD or depression. In this study, we examined the contribution of either innate hippocampal volume differences or hippocampal susceptibility to stress-induced shrinkage to the formation of stress-related psychopathology using longitudinal MRI measurements of hippocampal volume in inbred C57 mice before and after chronic social defeat stress. We found that only half of the stressed C57 mice were susceptible to stress and developed psychopathological behaviors such as social avoidance. The other half was resilient to stress and exhibited no social avoidance. Before exposure to stress, we observed a positive correlation between hippocampal volume and social avoidance. After chronic social defeat stress, we found significant increases in left hippocampal volume in resilient and nonstressed control mice. Intriguingly, this increase in hippocampal volume was not found in susceptible mice, suggesting an arrestment of hippocampal growth in these mice. Our findings suggest that both a susceptibility to stress-induced hippocampal volume changes and a larger hippocampus before stress exposure confer vulnerability to psychopathology after chronic stress.

10.1002/hipo.22296

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Citations (59)

The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner

Stem Cell Reports (2016)

Ayden Gouveia Karolynn Hsu Yosuke Niibori Matthew Seegobin Gonzalo I. Cancino

While epigenetic modifications have emerged as attractive substrates to integrate environmental changes into the determination of cell identity and function, specific signals that directly activate these epigenetic modifications remain unknown. Here, we examine the role of atypical protein kinase C (aPKC)-mediated Ser436 phosphorylation of CBP, a histone acetyltransferase, in adult hippocampal neurogenesis and memory. Using a knockin mouse strain (CbpS436A) in which the aPKC-CBP pathway is deficient, we observe impaired hippocampal neuronal differentiation, maturation, and memory and diminished binding of CBP to CREB in 6-month-old CbpS436A mice, but not at 3 months of age. Importantly, elevation of CREB activity rescues these deficits, and CREB activity is reduced whereas aPKC activity is increased in the murine hippocampus as they age from 3 to 6 months regardless of genotype. Thus, the aPKC-CBP pathway is a homeostatic compensatory mechanism that modulates hippocampal neurogenesis and memory in an age-dependent manner in response to reduced CREB activity.

CREB-binding protein

10.1016/j.stemcr.2016.08.007

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Citations (14)

Juvenile Administration of Methylphenidate Attenuates Adult Hippocampal Neurogenesis

Biological Psychiatry (2006)

Diane C. Lagace Jessica K. Yee Carlos A. Bolaños Amelia J. Eisch

10.1016/j.biopsych.2006.04.009

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Citations (80)

Short- and Long-term Exposure to Low and High Dose Running Produce Differential Effects on Hippocampal Neurogenesis

Neuroscience (2017)

Carine Nguemeni Matthew W. McDonald Matthew S. Jeffers Jessica M. Livingston‐Thomas Diane C. Lagace

10.1016/j.neuroscience.2017.11.026

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Citations (20)

Ascl1 defines sequentially generated lineage-restricted neuronal and oligodendrocyte precursor cells in the spinal cord

Development (2006)

James Battiste Amy W. Helms Euiseok J. Kim Trisha K. Savage Diane C. Lagace

The neural basic helix-loop-helix transcription factor Ascl1 (previously Mash1) is present in ventricular zone cells in restricted domains throughout the developing nervous system. This study uses genetic fate mapping to define the stage and neural lineages in the developing spinal cord that are derived from Ascl1-expressing cells. We find that Ascl1 is present in progenitors to both neurons and oligodendrocytes, but not astrocytes. Temporal control of the fate-mapping paradigm reveals rapid cell-cycle exit and differentiation of Ascl1-expressing cells. At embryonic day 11, Ascl1 identifies neuronal-restricted precursor cells that become dorsal horn neurons in the superficial laminae. By contrast, at embryonic day 16, Ascl1 identifies oligodendrocyte-restricted precursor cells that distribute throughout the spinal cord. These data demonstrate that sequentially generated Ascl1-expressing progenitors give rise first to dorsal horn interneurons and subsequently to late-born oligodendrocytes. Furthermore, Ascl1-null cells in the spinal cord have a diminished capacity to undergo neuronal differentiation, with a subset of these cells retaining characteristics of immature glial cells.

Fate mapping

OLIG2

GDF7

Precursor cell

Progenitor

10.1242/dev.02727

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Citations (167)