Neuroinflammation and the plasticity-related immediate-early gene Arc

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Abstract

Neurons exist within a microenvironment that significantly influences their function and survival. While there are many environmental factors that can potentially impact neuronal function, activation of the innate immune system (microglia) is an important element common to many neurological and pathological conditions associated with memory loss. Learning and memory processes rely on the ability of neurons to alter their transcriptional programs in response to synaptic input. Recent advances in cell-based imaging of plasticity-related immediate-early gene (IEG) expression have provided a tool to investigate plasticity-related changes across multiple brain regions. The activity-regulated, cytoskeleton-associated IEG Arc is a regulator of protein synthesis-dependent forms of synaptic plasticity, which are essential for memory formation. Visualisation of Arc provides cellular level resolution for the mapping of neuronal networks. Chronic activation of the innate immune system alters Arc activity patterns, and this may be a mechanism by which it induces the cognitive dysfunction frequently associated with neuroinflammatory conditions. This review discusses the use of Arc expression during activation of the innate immune system as a valid marker of altered plasticity and a predictor of cognitive dysfunction.

Highlight

► This review discusses the use of Arcexpression during activiation of the innate immune system as a valid marker of altered plasticity and a predictor of cognitive dysfunction.

Introduction

Who we are is determined by our perceptions and actions, which are largely guided by our memory; therefore, our ability to remember determines who we are as an individual. The ability of our brain to form and store new memories involves modulation of the strength and efficacy of synaptic signalling and is mediated by de novo synthesis of genes and proteins. Dysfunction of hippocampal synaptic plasticity results in loss of memory functions and is characteristic of many neurodegenerative diseases, such as Alzheimer’s disease, HIV-associated dementia, autism, Down syndrome and multiple sclerosis (Akiyama et al., 2000, Akiyama et al., 2001, Banati et al., 2000, McGeer and McGeer, 1998, Mhatre et al., 2004, Morganti-Kossmann et al., 2001, Vargas et al., 2005). Additionally, dysfunction of hippocampal synaptic plasticity may be a long term consequence of traumatic brain injury (TBI) (McAllister, 1992), therapeutic brain irradiation (Meyers et al., 2000) or normal ageing. Although neuronal dysfunction is the ultimate consequence of these disorders, alterations in the neuronal microenvironment, by activation of the innate immune system, seems to be the key factor for the progression of these pathologies (Akiyama et al., 2000, Akiyama et al., 2001, Banati et al., 2000, McGeer and McGeer, 1998, Mhatre et al., 2004, Morganti-Kossmann et al., 2001, Vargas et al., 2005).

Microglial cells are bone-marrow/mesenchymal-derived monocytes and constitute the resident innate immune system of the brain as well as the key cellular mediators of neuroinflammatory processes (Barger and Basile, 2001). Once activated, microglial cells release potentially harmful molecules, such as proinflammatory cytokines, chemokines, reactive oxygen species and complement proteins, leading to a self-propagating cycle and resulting in chronic neuroinflammation, which may compromise synaptic plasticity.

Synaptic plasticity requires de novo gene expression and protein synthesis for the development of enduring synaptic modifications and long-term changes in behaviour (Deisseroth et al., 2003, Lee et al., 2005). The immediate early gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) is expressed in response to synaptic activity in the principal neurons of different brain structures (cortex, hippocampus, amygdala and striatum). Arc expression is required for the formation of durable plasticity processes that underlie memory consolidation and correlates both temporally and spatially with the stimulus that induced its transcription (Guzowski et al., 2000, Lyford et al., 1995). The correspondence in circuit dynamics between electrophysiology and Arc expression has led to the suggestion that expression of Arc may serve as a reliable monitor of cellular activity, reflecting spatial and contextual information processing (Guzowski et al., 1999). As a result, Arc could be used to study altered hippocampal circuits (Rosi et al., 2009). It has been recently reported that dysregulation of Arc expression parallels cognitive dysfunctions observed in several different inflammatory-related conditions (Frank et al., 2010, Hein et al., 2010, Rosi et al., 2006). Arc dysregulation is also involved in the comorbidity of anxiety and alcohol drinking and the neuro-adaptation of drug addiction (Hearing et al., 2010, Lucas et al., 2008, Pandey et al., 2008). Understanding how neuroinflammation may affect synaptic plasticity is one of the most important goals for basic and clinical neuroscience. This review discusses the use of the plasticity-related behaviourally-induced Arc expression during neuroinflammatory conditions as a reliable marker for studying altered hippocampal circuits.

Section snippets

Brain inflammation

Neuroinflammation begins as a host defence mechanism associated with neutralisation of an insult and restoration of normal structure and function, similar to inflammation in peripheral organs. However, if neuroinflammation is not regulated, it can result in a self-propagating and deleterious process. Microglial cells are considered to be the resident immune system of the brain and react to various insults, such as viruses, bacteria, circulating pathogens, physical injury, chemical insults,

Arc, learning and memory

Memory formation is a temporally graded process, which requires transcription and translation in the first hours after acquisition (learning). The hippocampus is a brain region critical for the acquisition, consolidation and retrieval of declarative memories (for review, see Eichenbaum, 2001, Squire, 1994). This process involves modulation of the strength and efficacy of synaptic signalling (i.e., synaptic plasticity), which in turn involves de novo gene expression (Deisseroth et al., 2003).

Inflammation and Arc

Investigating how the hippocampus processes episodic memory information during neuropathological conditions is important for understanding their influence on cognition. Given the specificity and the well-characterised dynamics of behaviourally-induced Arc expression and its critical role in synaptic plasticity and memory, Arc represents a unique marker for assessing how pathological conditions affect specific neuronal functions associated with cognitive performance.

Normally, Arc protein

Neurogenesis, Arc and inflammation

The mechanisms underlying the cognitive impairments associated with inflammatory conditions are likely to be multifactorial, but one important possibility involves the process of hippocampal neurogenesis. Evidence supports the role of adult neurogenesis in neural plasticity underlying animal cognition. Neurogenesis in the DG has been shown to be required for hippocampus-dependent memory functions (Dupret et al., 2008, Imayoshi et al., 2008), and the number of newborn granule cells has been

Hippocampal circuits and activated microglia

Memory is a network phenomenon encoded by ensembles of neurons within specific brain areas, amongst which the hippocampus plays a crucial role. Hippocampal network function is essential for discrimination and retrieval of information and enables effective navigational behaviour. Given the correspondence in circuit dynamics between electrophysiological recordings and measurements of Arc, Arc expression can be used as a reliable monitor of cellular activity, reflecting spatial and contextual

Neuroinflammation and transcriptional regulation and translation of Arc

The changes in behaviourally-induced Arc during inflammatory conditions could result from (1) a failure in its transcriptional regulation and/or (2) failures in post-transcriptional mechanisms that control the amount of synthesis in response to synaptic input and/or (3) altered degradation of Arc after its induction.

Transcriptional regulation of Arc is activity-dependent and requires NMDAR activation, extracellular signal-regulated kinase (ERK) (Steward et al., 1998, Steward and Worley, 2001)

Summary and conclusions

In summary, in vivo studies have shown that, during brain inflammation, changes in hippocampus-dependent memory functions consistently correlate with the expression of plasticity-related, behaviourally-induced, IEG Arc. The changes in expression of behaviourally-induced Arc, described during different inflammatory conditions, further illustrate the strong link between activation of the innate immune system and altered synaptic plasticity and support the use of Arc as reliable marker to study

Acknowledgments

We would like to thank Professor Giancarlo Pepeu and Doctor Karim Belarbi for their critical feedback on the manuscript.

Grant sponsor: Alzheimer’s Association, NIH. Grant No.: NIRG 08-90589, R01 CA133216.

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