Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide

Mahar, Ian; Labonté, Benoit; Yogendran, Sandra; Isingrini, Elsa; Perret, Léa C.; Davoli, Maria Antonietta; Rachalski, Adeline; Giros, Bruno; Turecki, Gustavo; Mechawar, Naguib

doi:10.1038/tp.2017.132

Cited by 26 publications

(23 citation statements)

References 46 publications

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“…Altered production and survival of developmentally‐born DG neurons is also relevant for a number of disorders that are associated with large‐scale structural changes in the hippocampus, and sometimes the DG in particular, such as autism (Saitoh, Karns, & Courchesne, ; Schumann et al, ), schizophrenia (Lodge & Grace, ; Tamminga, Stan, & Wagner, ) and depression (McKinnon, Yucel, Nazarov, & MacQueen, ). For example, recent reports indicate that depressed patients have fewer total DG neurons in the anterior hippocampus, which can be restored by SSRI antidepressants (Boldrini et al, ; Mahar et al, ). While antidepressant treatments are often cited for their proneurogenic properties, our findings indicate that changes in the developmentally‐born cell population could also contribute to changes in total granule cell number.…”

Section: Discussionmentioning

confidence: 99%

Early survival and delayed death of developmentally‐born dentate gyrus neurons

Cahill

Dylan

et al. 2017

Hippocampus

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The storage and persistence of memories depends on plasticity in the hippocampus. Adult neurogenesis produces new neurons that mature through critical periods for plasticity and cellular survival, which determine their contributions to learning and memory. However, most granule neurons are generated prior to adulthood; the maturational timecourse of these neurons is poorly understood compared to adult-born neurons but is essential to identify how the dentate gyrus (DG), as a whole, contributes to behavior. To characterize neurons born in the early postnatal period, we labeled DG neurons born on postnatal day 6 (P6) with BrdU and quantified maturation and survival across early (1 hr to 8 weeks old) and late (2-6 months old) cell ages. We find that the dynamics of developmentally-born neuron survival is essentially the opposite of neurons born in adulthood: P6-born neurons did not go through a period of cell death during their immature stages (from 1 to 8 weeks). In contrast, 17% of P6-born neurons died after reaching maturity, between 2 and 6 months of age. Delayed death was evident from the loss of BrdU cells as well as pyknotic BrdU caspase3 neurons within the superficial granule cell layer. Patterns of DCX, NeuN, and activity-dependent Fos expression indicate that developmentally-born neurons mature over several weeks and a sharp peak in zif268 expression at 2 weeks suggests that developmentally-born neurons mature faster than adult-born neurons (which peak at 3 weeks). Collectively, our findings are relevant for understanding how developmentally-born DG neurons contribute to memory and disorders throughout the lifespan. High levels of early survival and zif268 expression may promote learning, while also rendering neurons sensitive to insults at defined stages. Late neuronal death in young adulthood may result in the loss of hundreds of thousands of DG neurons, which could impact memory persistence and contribute to hippocampal/DG atrophy in disorders such as depression.

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Section: Discussionmentioning

confidence: 99%

Early survival and delayed death of developmentally‐born dentate gyrus neurons

Cahill

Dylan

et al. 2017

Hippocampus

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“…Although, herein, the description of NRGs/ErbB-dependent roles in the modulation of synaptic plasticity has been focused on the hippocampus and midbrain DA nuclei, it should be considered that emerging evidence also documented NRGs-induced regulation of synaptic plasticity in other brain areas, and several reports mainly obtained in transgenic mice with altered NRGs/ErbB signaling support that the proper NRGs/ErbB tone (neither too much nor too little) is essential for various cognitive functions and behaviors. Since dysfunctions in NRGs/ErbB signaling have been linked to different neurological and psychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, genetic intellectual disabilities, AD, major depressive disorder, PD, and addiction [23,46,[136][137][138][139][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159], intense research efforts should be aimed at deciphering NRGs-dependent mechanisms causing pathological defects, as this might have noticeable implications on the understanding and treatment of different serious brain diseases.…”

Section: Conclusion and Outstanding Issuesmentioning

confidence: 99%

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity

Ledonne

Mercuri

2019

IJMS

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Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain’s pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3–CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.

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“…The functional relevance of this delayed cell death is unknown, but it could contribute to forgetting and hippocampal/DG atrophy in disorders such as depression (Boldrini et al, 2013;Mahar et al, 2017;McKinnon, Yucel, Nazarov, & MacQueen, 2009). Also, while adult-born neurons are stable after reaching 4 weeks of age, we found that 17% of P6-born neurons died between 2 and 6 months of age.…”

mentioning

confidence: 99%

“…Also, while adult-born neurons are stable after reaching 4 weeks of age, we found that 17% of P6-born neurons died between 2 and 6 months of age. The functional relevance of this delayed cell death is unknown, but it could contribute to forgetting and hippocampal/DG atrophy in disorders such as depression (Boldrini et al, 2013;Mahar et al, 2017;McKinnon, Yucel, Nazarov, & MacQueen, 2009). Whether delayed cell death is observed among cells born at ages other than P6 is unknown.…”

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confidence: 99%

Dentate gyrus neurons that are born at the peak of development, but not before or after, die in adulthood

2019

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IntroductionIn the dentate gyrus of the rodent hippocampus, neurogenesis begins prenatally and continues to the end of life. Adult‐born neurons often die in the first few weeks after mitosis, but those that survive to 1 month persist indefinitely. In contrast, neurons born at the peak of development are initially stable but can die later in adulthood. Physiological and pathological changes in the hippocampus may therefore result from both the addition of new neurons and the loss of older neurons. The extent of neuronal loss remains unclear since no studies have examined whether neurons born at other stages of development also undergo delayed cell death.MethodsWe used BrdU to label dentate granule cells that were born in male rats on embryonic day 19 (E19; before the developmental peak), postnatal day 6 (P6; peak), and P21 (after the peak). We quantified BrdU+ neurons in separate groups of rats at 2 and 6 months post‐BrdU injection to estimate cell death in young adulthood.ResultsConsistent with previous work, there was a 15% loss of P6‐born neurons between 2 and 6 months of age. In contrast, E19‐ or P21‐born neurons were stable throughout young adulthood.DiscussionDelayed death of P6‐born neurons suggests these cells may play a unique role in hippocampal plasticity adulthood, for example, by contributing to the turnover of hippocampal memory. Their loss may also play a role in disorders that are characterized by hippocampal atrophy.

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Disrupted hippocampal neuregulin-1/ErbB3 signaling and dentate gyrus granule cell alterations in suicide

Cited by 26 publications

References 46 publications

Early survival and delayed death of developmentally‐born dentate gyrus neurons

Early survival and delayed death of developmentally‐born dentate gyrus neurons

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity

Dentate gyrus neurons that are born at the peak of development, but not before or after, die in adulthood

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