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Neurochem Res. Author manuscript; available in PMC Nov 1, 2012.
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PMCID: PMC3478877

Neuroinflammation and synaptic loss


Neuroinflammation plays a critical role in the progression of many neurodegenerative diseases and neuropsychiatric illnesses. It is evident that microglia in particular are central to mediating the effects of neuroinflammation. Activated microglia release a number of cytokines and chemokines, which in turn activate many signal transduction pathways. For instance, interleukin-1 beta and tumor necrosis factor alpha regulate transcription of a number of genes within the brain including proinflammatory products of the arachidonic acid (AA) cascade. Co-activation of pro-inflammatory markers and associated cytotoxic products during neuroinflammation process are detrimental to neurons by altering the synaptic proteins. In this review, we discuss both neuroinflammation as well as excitotoxicity insults reduce synaptic markers such as synaptophysin and drebrin in rat brain. Further we discuss here, neurodegenerative and neuropsychiatric illness are associated with increased neuroinflammatory and excitotoxicity markers as well as upregulated brain arachidonic acid markers and the loss of synaptic markers. The decrease in synaptic markers might contribute to reported cognitive defects in neurodegenerative and neuropsychiatric illnesses.


It is becoming increasingly clear that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative and psychiatric illnesses including Alzheimer’s, Parkinson’s, Huntington’s disease, bipolar disorder, schizophrenia and depression (Bales et al, 2000; Dobos et al, 2010; Doorduin et al, 2009; Hunot and Hirsch, 2003; Rao et al, 2010; Silvestroni et al, 2009). Neuroinflammation is a complex combination of the responses of all cell types present within the central nervous system (CNS), including neurons, macroglia, microglia and infiltrating leukocytes. Infection, trauma, and toxins are capable of producing an immediate short lived induction of innate immune response within the CNS (Crutcher et al, 2006; Popovich and Longbrake, 2008). Acute neuroinflammation triggers activation of resident microglia and the release of inflammatory mediators such as cytokines and chemokines (Tansey et al, 2007). Acute insult is typically short-lived and unlikely to be harmful to long term neuronal survival. It is believed that an acute neuroinflammatory response is generally beneficial to the CNS, since it tends to minimize further injury and contributes to repair of damaged tissue. On the other hand chronic inflammation produces long lasting and self perpetuating neuroinflammatory mediators that remain after the initial neuroinflammatory insult.

Neuroinflammation: induction of proinflammatory cytokines and arachidonic acid cascade enzymes

During neuroinflammation, proinflammatory cytokines such as interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα), IL-6 and chemokines including interferon gamma, macrophage inflammatory protein and inducible protein (IP)-10 are released by activated microglia that promote neuroinflammatory state. IL-1β and TNFα regulate expression of many genes, including gene transcription for arachidonic acid (AA) cascade enzymes in various cell types via nuclear kappa B (NF-κB) or AP-2 (Acarin et al, 2002; Bauer et al, 1997; Hoeck et al, 1993; Jupp et al, 2003; Spriggs et al, 1990). In the brain, AA and its metabolites influence signal transduction, gene transcription, neuronal activity, apoptosis, and other processes (Kam and See, 2000; Leslie and Watkins, 1985; O’Banion, 1999). AA released from membrane phospholipids by Ca2+-dependent cytosolic phospholipase A2 (cPLA2-IVA), secretory (sPLA2 IIA), or Ca2+- independent (iPLA2 VIA), which differ in their calcium requirement, phosphorylation, and substrate specificities (Akiba et al, 1999; Murakami et al, 1999; Murakami and Kudo, 2002; Murakami et al, 1998; Yang et al, 1999). The released AA can be metabolized to prostaglandin (PG)H2 by cyclooxygenase (COX)-1 or COX-2, converted to cytoprotective epoxyeicosatrienoic acids by cytochrome p450 epoxygenase or to cytotoxic leukotrienes by 5, −12 or −15 lipoxygenase (LOX) (Funk, 2001). PGH2 is converted to PGE2 by membrane prostaglandin E synthase (mPGES) or cytosolic PGES (cPGES), or by thromboxane synthase (TXS) to TXA2. COX-1 and cPGES are expressed constitutively in the brain, whereas COX-2 and mPGES are inducible (Pepicelli et al, 2002; Seibert et al, 1995) (Figure-1).

Figure 1
Schematic representation of arachidonic acid cascade

Cross-talk between neuroinflammation and excitotoxicity

Neuroinflammatory markers and AA cascade markers are elevated by excitotoxicity. For instance, activated microglia release nitric oxide which blocks reuptake of glutamate at the presynaptic site, which results in excessive glutamate at the synaptic cleft and activation of NMDA receptors. It is well known that excessive glutamate levels causes excitotoxicity. Activation of NMDA receptors activates AA turnover via upregulation of cPLA2 activity, protein and mRNA levels in an AP-2 dependent manner (Rao et al, 2007b). In addition, chronic NMDA administration to rats upregulates levels of proinflammatory IL-1β, TNFα, glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) in rat brains (Chang et al, 2008b). Altogether finding suggests that there is cross-talk between neuroinflammation and excitotoxicity that involves release of AA products in the brain. Upregulation of neuroinflammatory and AA cascade markers in chronic NMDA administrated rat has been shown to cause neuronal loss (Kim et al, 2009a). This suggests that both neuroinflammation and associated elevated AA cascade are detrimental to neuronal survival. In those conditions synaptic markers (synaptophysin and drebrin) are also prone to damage.

Synaptic proteins

Drebrin is an actin-binding protein neuron-specific isoform (Kojima et al, 1988), abundantly found within dendritic spines that are located at postsynaptic excitatory synapses (Aoki et al, 2005). Drebrin expression was found to be maximal during embryogenesis and decreases thereafter (Shirao, 1995). The over expression of drebrin provokes the elongation of spines in mature neurons (Hayashi and Shirao, 1999) and the change of dendritic filopodia into aberrantly enlarged megapodia in immature neurons (Mizui et al, 2005). Conversely, the suppression of drebrin expression reduces spine density and results in the formation of thin immature spines (Takahashi et al, 2006). These findings support the idea that the drebrin–actin complex plays a crucial role in the regulation of dendritic spine morphology.

Synaptophysin is a 38-kd glycoprotein localized in synaptic vesicle membranes. The main functions of synaptophysin include docking, fusion, and endocytosis, otherwise known as membrane trafficking (Evans and Cousin, 2005).

Neuroinflammation: synaptic protein loss

Neurodegenerative disease

Hatanpaa and others reported decreased cortical drebrin in Alzheimer’s as well as normal aging (Hatanpaa et al, 1999). Studies also report that drebrin is decreased in postmortem hippocampal (Harigaya et al, 1996) and temporal (Counts et al, 2006) regions obtained from severe and mildly cognitively impaired patients. In Alzheimer disease (AD), neuroinflammation plays a role in altering the neuronal synaptic proteins. In recent year’s decreased drebrin have been shown to correlate with cognitive impairment in patients with Alzheimer disease (AD) (Counts et al, 2006; Kobayashi et al, 2004; Kojima and Shirao, 2007; Zhao et al, 2006). The decreased drebrin in AD might be due to upregulated neuroinflammatory and AA cascade markers, since an excess of neuroinflammatory markers such as TNFα, IL-1β and AA have been shown to damage neurons by increasing pro-apoptotic marker and caspase 3 activities (Fang et al, 2008; Gibson et al, 2004; Zhu et al). It is possible that elevated AA alone or in combination with neuroinflammation might be involved in reducing the synaptic proteins. Upregulated neuroinflammation, AA cascades and reduced drebrin can occur in bipolar disorder (Kim et al, 2009b; Rao et al), HIV-1 transgenic rat (Basselin et al), schizophrenia (Rao et al upublished data) and in n-3 polyunsaturated fatty acid deprived animals (Rao et al, 2007a).

Synaptophysin has been shown to be reduce during aging (Haley et al) as well as in neurodegenerative disease including AD (Hamos et al, 1989).

Neuropsychiatric illness

Postmortem brains from bipolar disorder (BD) and schizophrenic patients showed upregulated neuroinflammatory markers and AA cascade markers as well as decreased synaptic markers (drebrin and synaptophysin) (Glantz and Lewis, 1997a, b; Kim et al, 2009b; Rao et al). Cognitive impairment has been reported in BD and SZ patients (Wingo et al, 2009; Wobrock et al, 2009).

Animal models of neuroinflammation

Similar to clinical studies, in animal models of neuroinflammation such as a non-infectious rat model of HIV-1 and rats treated with a high dose of lipopolysaccharide (LPS) (200 ng/hr) infusion for six days both exhibited upregulated neuroinflammatory markers TNFα, and cd11b and also exhibited decreased protein and mRNA levels of drebrin and synaptophysin (Rao et al 2009; Kellom et al unpublished data)(figure-1 and and2).2). In both models there are upregulated AA cascade markers (Rao et al 2009; Kellom et al unpublished data). However, low dose infusion of LPS (0.5ng/hr) for six days increased TNF alpha protein level without a significant change in cPLA2 transcription or drebrin protein in rat brain. This suggests that TNFα alone cannot decrease drebrin levels in rat brain. In combination, these findings suggest neuroinflammation associated with AA signaling could downregulate drebrin levels in rat brain.

Figure 2
Representation of cross-talk between neuroinflammation and excitotoxicity involving arachidonic acid cascade.


In a model of excitotoxicity, an intense stimulation of NMDA results in drebrin loss in cultured hippocampal neurons (Halpain et al, 1998). Chronic NMDA administration to rats upregulates brain AA turnover with increased cPLA2 activity and cPLA2 transcription in rat brain. Chronic NMDA exposure in rats result in upregulated protein and mRNA levels of neuroinflammatory markers such as IL-1β, TNF α, GFAP and iNOS in rat frontal cortex (Chang et al, 2008a). These studies imply that excitotoxicity and neuroinflammation signaling pathways cross-talk with each other and involve AA signaling. Further, chronic NMDA administration to rats, results in upregulation of pro-apoptotic factors Bad and Bax which causes neuronal loss (Kim et al, 2009a). The combination of neuroinflammation and AA signaling could influence the synaptic loss.

N-3 polyunsaturated dietary deprivation model

Clinical and pre-clinical studies support the idea that neuroinflammation associated AA cascade signaling results in synaptic loss. A recent study of triple transgenic AD mice has shows that n-3 polyunsaturated fatty acid(PUFA) dietary deprivation in mice reduces brain drebrin levels (Julien et al, 2008). Dietary n-3 deprivation in rats shows upregulated brain AA signaling with increased activity and transcription of both cPLA2 and sPLA2 (Rao et al, 2007a). This finding suggests either neuroinflammation or AA cascade increase could influence the reduction of the synaptic proteins in brain. The role of neuroinflammation or AA influence on synaptic proteins loss is not clear. It is apparent that drebrin is regulated by the transcriptional factor NXF and is modulated by DHA via phosphotidyl inositol kinase (Calon et al, 2004; Ooe et al, 2004). It perhaps AA may be act on this kinase and transcription factor of drebrin which could result in the reduction of drebrin transcription. A recent study demonstrate that cPLA2 inhibitor protects against prion and amyloid beta 1-42 induced synaptic loss in cultured rat cortical and hippocampal neurons (Bate et al). Further detailed molecular studies are needed to understand the role of proinflammatory AA and its metabolites effects on the drebrin and synaptophysin transcription factors.


The classical antidepressant fluoxetine, upon chronic administration to rats, upregulates hippocampal drebrin level compared with the chronically stressed group (Yang et al, 2003). Unlike antidepressants, antipsychotic drugs, olanzapine and haloperidol did not significantly change the hippocampal drebrin level in monkeys (Hill et al, 2006). Thus suggests drebrin is modulated by various factors including neuroinflammatory markers. The influence of AA on drebrin transcription is not clear. Further studies are warranted to understand the role of neuroinflammation and AA on drebrin regulation.


Neuroinflammatory and arachidonic acid markers are associated with synaptic protein loss of drebrin and synaptophysin. These changes could contribute to cognitive impairments in neurodegenerative and neuropsychiatric illnesses.

Figure 3
Representative immunoblot of drebrinand synaptophysinprotein levelsincontrol, low-dose LPS (0.5 ng/h) and high-dose LPS (250 ng/h) six-day infused rats. Data are ratios of optical density of drebrin and synaptophysin to β-actin, expressed as percent ...


This research was entirely supported by the Intramural Research Programs of the National Institute on Aging, National Institutes of Health, Bethesda, MD 20892. We thank the National Cancer Institute (NCI), Center for Cancer Research (CCR) Fellows Editorial Board and Dr. Ed Reese, for proofreading the manuscript.


arachidonic acid
Alzheimer disease
bipolar disorder
cytosolic prostaglandin E synthase
calcium-dependent phospholipase A2
glial fibrillary acidic protein
glycoprotein 120
human immunodeficiency virus
HIV-associated dementia
calcium-independent phospholipase A2
membrane prostaglandin E synthase
nuclear factor-kappa B
secretory phospholipase A2
tumor necrosis factor α
thromboxane synthase


Conflict of interest: No


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