Spatial reference memory deficits precede motor dysfunction in an experimental autoimmune encephalomyelitis model: The role of kallikrein–kinin system

Dutra, Rafael C.; Moreira, Eduardo Luiz Gasnhar; Alberti, Thaís; Marcon, Rodrigo; Prediger, Rui Daniel; Calixto, João B.

doi:10.1016/j.bbi.2013.06.002

Cited by 41 publications

(16 citation statements)

References 67 publications

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“…They showed a synaptic dysfunction in the hippocampal CA1 area, with a selective impairment in the ability to express LTP at two different time points post-immunization (13-16 days and 25-35 days), corresponding approximately to two disability stages (peak and milder). Interestingly, even before motor deficits became evident, mice manifested deficits in spatial learning [78], an evidence also confirmed by other groups [79] consistent with the hypothesis of a latent hippocampal dysfunction during the earlier phases of the disease, just after the beginning of the inflammatory process induced by the administration of the myelin-specific immunological trigger. As an attempt to reverse the observed synaptic deficit, authors fed EAE mice with a ketogenic diet [78].…”

Section: Hippocampal Synaptic Plasticity In Experimental Models Of Mssupporting

confidence: 68%

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Mancini

Gaetani

Gregorio

et al. 2017

Mult Scler Demyelinating Disord

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Cognitive impairment is very frequent during multiple sclerosis (MS), involving approximately 40-70% of the patients, with a profound impact on patient's life. It is now established that among the various central nervous system (CNS) structures involved during the course of MS, the hippocampus is particularly sensitive to the detrimental effects of neuroinflammation. Different studies demonstrated hippocampal involvement during MS, in association with depression and cognitive impairment, such as verbal and visuo-spatial memory deficits, even during the earlier phases of the disease. These cognitive alterations could represent the visible consequences of a hidden synaptic impairment. Indeed, neuronal and immune functions are intertwined and the immune system is able to modulate the efficacy of synaptic transmission and the induction of the main forms of synaptic plasticity, such as long term potentiation (LTP). Hippocampal synaptic plasticity has been studied during the last decades as the physiological basis of human learning and memory and its disruption can be associated with behavioral and cognitive abnormalities. The aim of the present work is to review the available evidence about the presence of hippocampal synaptic plasticity alterations in experimental models of MS, specifically during the course of experimental autoimmune encephalomyelitis (EAE) and to discuss their relevance with regard to human MS. Indeed, the failure of synapses to express plasticity during neuroinflammation could potentially lead to a progressive failure of the brain plastic reserve, possibly contributing to disability progression and cognitive impairment during MS.

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Section: Hippocampal Synaptic Plasticity In Experimental Models Of Mssupporting

confidence: 68%

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Mancini

Gaetani

Gregorio

et al. 2017

Mult Scler Demyelinating Disord

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“…The most common EAE scoring system is a scale ranging from 0 to 5 (Chen et al, 2014; Dutra et al, 2013; Mangiardi et al, 2011; Martin et al, 2016; Saijo et al, 2011; Smith-Bouvier et al, 2008; Tiwari-Woodruff et al, 2007). Some studies use a 8, 10 or 16 point scale (Bittner et al, 2014; Chakrabarty et al, 2004; Deslauriers et al, 2011; Emerson et al, 2009; Gold et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

Hasselmann

Karim

Khalaj

et al. 2017

Journal of Neuroscience Methods

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Background While many groups use experimental autoimmune encephalomyelitis (EAE) as a model to uncover therapeutic targets and understand the pathology underlying multiple sclerosis (MS), EAE protocol variability introduces discrepancies in central nervous system (CNS) pathogenesis and clinical disease, limiting the comparability between studies and slowing much-needed translational research. Optimized method Here we describe a detailed, reliable protocol for chronic EAE induction in C57BL/6 mice utilizing two injections of myelin oligodendrocyte glycoprotein (35–55) peptide mixed with Complete Freund’s Adjuvant and paired with pertussis toxin. Results The active MOG35–55 EAE protocol presented here induces ascending paralysis in 80–100% of induced mice. We observe: (1) consistent T cell immune activation, (2) robust CNS infiltration by peripheral immune cells, and (3) perivascular demyelinating lesions concurrent with axon damage in the spinal cord and various brain regions, including the optic nerve, cortex, hippocampus, internal capsules, and the cerebellum. Comparison with existing method(s) Lack of detailed protocols, combined with variability between laboratories, make EAE results difficult to compare and hinder the use of this model for therapeutic development. We provide the most detailed active MOG35–55-EAE protocol to date. With this protocol, we observe high disease incidence and a consistent, reliable disease course. The resulting pathology is MS-like and includes optic neuritis, perivascular mononuclear infiltration, CNS axon demyelination, and axon damage in both infiltrating lesions and otherwise normal-appearing white matter. Conclusions By providing a detailed active MOG35–55-EAE protocol that yields consistent and robust pathology, we aim to foster comparability between pre-clinical studies and facilitate the discovery of MS therapeutics.

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“…Consistent with such a view, we presently report that mice lacking IFN-γ showed disturbed spatial recognition memory in the basal state. Interestingly, Baron et al (2008) revealed that limited central overexpression of IFN-γ resulted in improved hippocampus-dependent memory, whereas pathologically elevated concentrations of the cytokine have generally been associated with memory impairment ( Lapter et al, 2009 ; Dutra et al, 2013 ; Too et al, 2014 ). Thus, when considered together, these data suggest that the hormetic-like dose-response pattern that was described elsewhere for memory and IL-1β (and several other immune actors; Yirmiya and Goshen, 2011 ) may very well be relevant too for IFN-γ.…”

Section: Discussionmentioning

confidence: 99%

IFN-Î³ differentially modulates memory-related processes under basal and chronic stressor conditions

Litteljohn

Nelson

Hayley

2014

Front. Cell. Neurosci.

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Cytokines are inflammatory messengers that orchestrate the brain’s response to immunological challenges, as well as possibly even toxic and psychological insults. We previously reported that genetic ablation of the pro-inflammatory cytokine, interferon-gamma (IFN-γ), attenuated some of the corticosteroid, cytokine, and limbic dopaminergic variations induced by 6 weeks of exposure to an unpredictable psychologically relevant stressor. Presently, we sought to determine whether a lack of IFN-γ would likewise modify the impact of chronic stress on hippocampus-dependent memory function and related neurotransmitter and neurotrophin signaling systems. As predicted, chronic stress impaired spatial recognition memory (Y-maze task) in the wild-type animals. In contrast, though the IFN-γ knockouts (KOs) showed memory disturbances in the basal state, under conditions of chronic stress these mice actually exhibited facilitated memory performance. Paralleling these findings, while overall the KOs displayed altered noradrenergic and/or serotonergic activity in the hippocampus and locus coeruleus, norepinephrine utilization in both of these memory-related brain regions was selectively increased among the chronically stressed KOs. However, contrary to our expectations, neither IFN-γ deletion nor chronic stressor exposure significantly affected nucleus accumbens dopaminergic neurotransmission or hippocampal brain-derived neurotrophic factor protein expression. These findings add to a growing body of evidence implicating cytokines in the often differential regulation of neurobehavioral processes in health and disease. Whereas in the basal state IFN-γ appears to be involved in sustaining memory function and the activity of related brain monoamine systems, in the face of ongoing psychologically relevant stress the cytokine may, in fact, act to restrict potentially adaptive central noradrenergic and spatial memory responses.

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Spatial reference memory deficits precede motor dysfunction in an experimental autoimmune encephalomyelitis model: The role of kallikrein–kinin system

Cited by 41 publications

References 67 publications

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Hippocampal neuroplasticity and inflammation: relevance for multiple sclerosis

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

IFN-Î³ differentially modulates memory-related processes under basal and chronic stressor conditions

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