Short surveyCytokines and cytokine networks target neurons to modulate long-term potentiation
Introduction
Brain plasticity underlies our ability to learn and modify our behavior, and can be compromised in neuropsychiatric and neurodegenerative diseases. Brain plasticity relies on synaptic plasticity, which strengthens or weakens synapses. One of the most widely used models for studying molecular mechanisms of synaptic plasticity is long-term potentiation (LTP), a cellular correlate of memory characterized by a rapid and remarkably persistent increase in synaptic transmission elicited by brief patterns of afferent activity [1]. Experimental support that LTP is causally linked to synaptic processes underlying memory continues to build [2], [3]. Notably, a recent study demonstrated that fear conditioning (a type of associative memory) can be inactivated and reactivated by long-term depression (LTD) and LTP respectively [4], supporting a causal link between these synaptic processes and memory. The critical elements for establishing LTP involve membrane depolarization and NMDA receptors (NMDAR) activation [2], which allows calcium influx [5], activation of intracellular pathways (e.g., calcium/calmodulin kinases, PKA, and the Rac/Pak/LIMK cascade), and morphological adaptations in spines that are essential for stable LTP [6]. LTP can be modulated by soluble messengers of the brain, such as cytokines and classic neuromodulators (e.g., norepinephrine, dopamine and acetylcholine). While the role of classic neuromodulators on LTP has been extensively studied, the effects of cytokines on LTP are relatively unexplored. Importantly, a growing body of evidence indicates that cytokine networks modulate LTP under both physiological and pathological conditions [7]. In this review, we illustrate examples of direct vs indirect modulation of synaptic transmission and LTP by cytokines. We show that cytokines can directly target synapses, and present a novel approach using isolated synaptosomes which allows the study of LTP directly at the synapse. We conclude with a perspective on strategies for dissecting the identity of cytokines able to modulate LTP directly in neurons. The information provided by these novel approaches may reveal key nodes on the topology of brain cytokine-cell networks.
Cytokines constitute an extremely elaborated network of peptide signaling molecules (∼5–20 kDa) that are fundamental in cell signaling. Cytokines act through receptors, and are especially important for immune cells, which synthesize and release cytokines in response to infections or tissue damage. Notably, the pattern of released cytokines depends on the nature of the antigenic stimulus, and the cell source that is being stimulated [8]. A number of factors further contribute to the high complexity of cytokine-cell networks. A prominent factor is the cytokine’s pleiotropy nature, by which a given cytokine can induce differential, even opposite cell responses [9], [10]. In addition, cytokines can cross-talk with signaling from other soluble factors; a cross-talk that is time, concentration and tissue-specific [10]. When acting on the brain, cytokines can induce fever, sleep and sickness behavior; they can also modify the mood, memory consolidation and cognition, as well as regulate neuroendocrine stress responses [8]. Indeed, a large number of cytokines can be released under multiple physiological and pathological contexts including learning, arousal, stress and neurodegeneration [7]. Brain cytokine levels are generally low at physiological-basal conditions but dramatically increase in response to infection, pathology (e.g., Aβ, α-synuclein) or damage (e.g., damage-associated molecular patterns, PAMP’s). Based on the emerging understanding that inflammation-mediated signaling leads to cognitive deficits [11], [12], it is commonly believed that neuronal functions can be impaired by high concentrations of inflammatory cytokines (e.g., IL-1β, IL-6, IL-18, tumor necrosis factor-α (TNFα), interferon (IFN)-α and IFNγ), whereas anti-inflammatory cytokines (e.g., IL-4, and IL-10) could have a protective role [13].
Inflammatory cytokines impair neuronal function in the adult brain by their direct effect on neurons or by indirect mechanisms mediated by non-neuronal cells (e.g., microglia and astrocytes). The effects of inflammatory cytokines on brain mechanisms have been studied in vitro using brain slices [14], [15], as well as in vivo by systemic treatment [16], direct infusion in the brain [17], [18], and by transgenic cytokine overexpression [19], [20]. In these experimental systems, elucidating neuron-specific effects of cytokines has been challenging because both neurons and non-neuronal brain cells commonly express cytokine receptors [21]. Moreover, cytokines can induce the expression and release of multiple cytokines in their target cells [20], [21], [22], [23], [24], thus increasing the complexity of the stimuli sensed by neurons after a challenge with a single cytokine (Fig. 1). Clarification of the brain cytokine networks and how their final effectors impact neuronal activity directly during both physiological and pathological contexts may help to identify specific therapeutic targets for inflammation-related cognitive decline.
Section snippets
Modulation of synaptic transmission by cytokine-cell networks
Cytokine networks are composed of the cytokine themselves, their receptors and their regulators. In the brain, cytokine networks are fundamental for the dynamic interaction between neurons, glia, endothelial cells, and immune cells including monocytes and lymphocytes (Fig. 1). Immune cells reach the CNS via blood [10] and, potentially, via the recently discovered meningeal lymphatic vessels [25]. At the synapse, the central element of neural connectivity, pre- and post-synaptic elements
Suppression of LTP by cytokines
Recent reports have shown that the Nlrp3 inflammasome controls systemic inflammation in both brain and periphery [29], [30]. Following Nlrp3 inflammasome activation, caspase-1 can cleave the precursors of IL-1β and IL-18, thus converting these cytokines into mature forms that can be secreted from the cell. In rodents, in vivo [31], [32] and in vitro [14], [15] electrophysiological recordings have shown that IL-1β suppresses LTP in the hippocampus, a brain region containing key neuronal
Facilitation of LTP by cytokines
In apparent contradiction with clinical studies showing that cytokine-driven neuroinflammation contributes to Alzheimer’s disease and other neurodegenerative diseases [11], [12], [47], there is evidence that inflammatory cytokines may play physiological roles in the healthy brain (i.e., in the absence of immune challenges or age-related inflammation). For instance, TNFα has been involved in AMPA receptor scaling, a homeostatic (non-Hebbian) form of plasticity that regulates neuronal firing rate
Experimental systems to study LTP modulation by neuron-targeting cytokines
LTP has been studied for decades both in vivo and in vitro, primarily in the hippocampus [60]. A number of induction protocols can be used to generate hippocampal LTP; most commonly, a train of electrical stimulation bursts separated by the period of the theta wave is used to initiate LTP in vivo or in brain slices. Although electrophysiological recordings in vivo and in brain slices might better reflect LTP responses found in intact brain circuitries, these approaches are not appropriate for
Synaptosomes provide an approach to study LTP modulation directly at the synapse
In spite of the advantages of primary neuronal cultures, this experimental system has some limitations. The main disadvantage is that cultured neurons develop in an artificial environment and may not embody all the properties of mature neurons including activity-dependent responses [75]. An alternative to neuronal cultures may be to use synaptosomal preparations (presynaptic terminals attached to postsynaptic structures), which can be isolated from adult and even aged animals, thus offering the
Concluding remarks
Along with classical neuromodulators, cytokines modulate synaptic plasticity via complex cytokine-cell networks. The complexity of brain cytokine networks reflects cytokines’ feedback loops, pleiotropy and cross-talk; and that most, if not all, brain cells are responsive to cytokines. It is commonly believed that inflammatory cytokines facilitate and impair neuronal functions at physiological-low and pathological-high concentrations, respectively. However, the timing and sequence of cytokine
Conflict of interest
The authors declare no competing financial interests.
Acknowledgements
Work in the authors’ lab is supported by National Institutes of Health Grants R21-AG048506, P01-AG000538 and RO1-AG34667 (to C.W.C.), UC MEXUS-CONACYT Grant CN-16-170 (to G.A.P. and C.W.C.).
Dr. G. Aleph Prieto is an Early-Stage Investigator focused on mechanisms of synaptic plasticity. Dr. Prieto studied biochemistry (B.Sc.), immunology (Master) and neuroscience (PhD) at the National Autonomous University of Mexico (UNAM). Currently, his work aims to dissect molecular pathways involved in synaptic dysfunction in aging and Alzheimer’s disease with the ultimate goal of finding therapeutic strategies to prevent brain impairment. Dr. Prieto has recently developed flow synaptometry
References (85)
- et al.
Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning
Brain Res.
(2015) - et al.
Immune modulation of learning, memory, neural plasticity and neurogenesis
Brain Behav. Immun.
(2011) Neuroinflammatory changes negatively impact on LTP: a focus on IL-1beta
Brain Res.
(2015)- et al.
Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus
Brain Res.
(1993) - et al.
Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus
Behav. Brain Res.
(2002) - et al.
A dual role for interleukin-1 in hippocampal-dependent memory processes
Psychoneuroendocrinology
(2007) - et al.
Sustained expression of interleukin-1beta in mouse hippocampus impairs spatial memory
Neuroscience
(2009) - et al.
Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice
Brain Behav. Immun.
(2010) Cytokines regulate expression of the type 1 interleukin-1 receptor in rat hippocampal neurons and glia
Exp. Neurol.
(2001)- et al.
Neuroinflammatory TNFalpha impairs memory via astrocyte signaling
Cell
(2015)
Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging
Cell Metab.
The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro
Neuroscience
A central nervous system-restricted isoform of the interleukin-1 receptor accessory protein modulates neuronal responses to interleukin-1
Immunity
Distinct expressions of three cytokines by IL-1-stimulated astrocytes in vitro and in AIDS brain
Brain Behav. Immun.
IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats
Brain Behav. Immun.
Interleukin-1beta causes long-term potentiation deficiency in a mouse model of septic encephalopathy
Neuroscience
Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain
Neurobiol. Aging
Neuroinflammation in Alzheimer’s disease
Lancet Neurol.
Impairment of recognition memory in interleukin-6 knock-out mice
Eur. J. Pharmacol.
Analysis of cognition, motor performance and anxiety in young and aged tumor necrosis factor alpha receptor 1 and 2 deficient mice
Behav. Brain Res.
Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain
J. Neuroimmunol.
Suppression of PKR promotes network excitability and enhanced cognition by interferon-gamma-mediated disinhibition
Cell
A dual role for interleukin-1 in LTP in mouse hippocampal slices
J. Neuroimmunol.
AMPARs and synaptic plasticity: the last 25 years
Neuron
Rapamycin and interleukin-1beta impair brain-derived neurotrophic factor-dependent neuron survival by modulating autophagy
J. Biol. Chem.
Caged neuron MEA: a system for long-term investigation of cultured neural network connectivity
J. Neurosci. Methods
Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons
Neuron
LTP requires a unique postsynaptic SNARE fusion machinery
Neuron
Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons
Neuron
Synaptic amyloid-beta oligomers precede p-tau and differentiate high pathology control cases
Am. J. Pathol.
Evaluation of glutamate as a hippocampal neurotransmitter: glutamate uptake and release from synaptosomes
Brain Res.
Temporal profile of M1 and M2 responses in the hippocampus following early 24 h of neurotrauma
J. Neurol. Sci.
Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences
Neurobiol. Learn Mem.
A cytokine network involving brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and TNFalpha operates during long-term potentiation and learning
Brain Behav. Immun.
A synaptic model of memory: long-term potentiation in the hippocampus
Nature
Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5
Nature
Learning induces long-term potentiation in the hippocampus
Science
Engineering a memory with LTD and LTP
Nature
Intracellular injections of EGTA block induction of hippocampal long-term potentiation
Nature
The links between the neuroendocrine and the immune systems: views of an immunologist
Cytokines in context
J. Cell Biol.
Cytokine networks in neuroinflammation
Nat. Rev. Immunol.
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Dr. G. Aleph Prieto is an Early-Stage Investigator focused on mechanisms of synaptic plasticity. Dr. Prieto studied biochemistry (B.Sc.), immunology (Master) and neuroscience (PhD) at the National Autonomous University of Mexico (UNAM). Currently, his work aims to dissect molecular pathways involved in synaptic dysfunction in aging and Alzheimer’s disease with the ultimate goal of finding therapeutic strategies to prevent brain impairment. Dr. Prieto has recently developed flow synaptometry approaches to study synapse phenotype and functionality. These highly innovative methods can evaluate synaptic plasticity in the human brain, a previously unattainable goal.
Dr. Carl W. Cotman is the Founding Director of the UC Irvine Institute for Memory Impairments and Neurological Disorders (formerly the Institute for Brain Aging and Dementia). His research is focused on identifying and testing interventions to reduce the rate of cognitive decline and promote successful brain aging. He was the first to discover that exercise increases brain derived neurotrophic factor (BDNF). His work has also provided crucial information about the mechanisms causing neuronal degeneration in Alzheimer's disease (AD) and has been pivotal for developing interventions to promote successful aging such as exercise. Notably, Dr. Cotman has authored more than 700 peer-review scientific articles. H-index: 159, Citations: 100921 (Google Scholar, March 2017).