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. Author manuscript; available in PMC: 2011 Sep 16.
Published in final edited form as: J Neurosci. 2011 Mar 16;31(11):4274–4279. doi: 10.1523/JNEUROSCI.5818-10.2011

Aging and a Peripheral Immune Challenge Interact To Reduce mBDNF and Activation of TrkB, PLCγ1, and ERK in Hippocampal Synaptoneurosomes

Giuseppe P Cortese 1, Ruth M Barrientos 1, Steven F Maier 1, Susan L Patterson 1
PMCID: PMC3086395  NIHMSID: NIHMS279952  PMID: 21411668

Abstract

For reasons that are not well understood, aging significantly increases brain vulnerability to challenging life events. High functioning older individuals often experience significant cognitive decline after an inflammatory event such as surgery, infection or injury. We have modeled this phenomenon in rodents, and have previously reported that a peripheral immune challenge (intraperitoneal injection of live E. coli) selectively disrupts consolidation of hippocampus-dependent memory in aged (24-month-old), but not young (3-month-old) F344xBN rats. More recently, we have demonstrated that this infection-evoked memory deficit is mirrored by a selective deficit in long-lasting synaptic plasticity in the hippocampus. Interestingly, these deficits occur in forms of long-term memory and synaptic plasticity known to be strongly dependent on BDNF.

Here, we begin to test the hypothesis that the combination of aging and an infection might disrupt production or processing of BDNF protein in the hippocampus, decreasing the availability of BDNF for plasticity-related processes at synaptic sites. We find that mature BDNF is markedly reduced in Western blots of hippocampal synaptoneurosomes prepared from aged animals following infection. This reduction is blocked by intra-cisterna magna administration of the anti-inflammatory cytokine IL-1Ra. Levels of the pan-neurotrophin receptor p75NTR and the BDNF receptor TrkB are not significantly altered in these synaptoneurosomes, but phosphorylation of TrkB and downstream activation of PLCγ1 and ERK are attenuated – observations consistent with reduced availability of mBDNF to activate TrkB signaling. These data suggest that inflammation-evoked reductions in BDNF at synapses might contribute to inflammation-evoked disruptions in long-term memory and synaptic plasticity in aging.

Keywords: Aging, Inflammation, Interleukin-1, LTP, Memory, and Hippocampus

Introduction

Aging is associated with increased variability in cognitive functioning - in part because aging brains are more vulnerable to negative life events such as infections, surgery, and stress (Wofford et al., 1996; Bekker and Weeks, 2003; VonDras et al., 2005). We have recently developed a rodent model to study the mechanisms involved in this vulnerability (Barrientos et al., 2006). Twenty-four month old Fischer-Brown Norway rats are aged, but not senescent; they generally do not show significant physical or cognitive impairments. However, in response to signals triggered by activation of the peripheral innate immune system (by an i.p. injection of E. coli), they show an exaggerated inflammatory response in the brain. Following the immune challenge, hippocampal production of the proinflammatory cytokine interleukin-1beta (IL-1β) is potentiated and prolonged in the aging rats relative to their younger (3-month-old) counterparts (Barrientos et al., 2009b). This exaggerated elevation in IL-1beta does not compromise initial learning or formation of short-term memories, nor does it disrupt basal synaptic function or short-term synaptic plasticity – instead it is paralleled by specific deficits in hippocampus-dependent long-term memory tasks (e.g. contextual fear and place learning) and theta burst-evoked late phase long-term potentiation (L-LTP) (Barrientos et al., 2009b; Chapman et al., 2010). Conversely, blocking IL-1 signaling in the brain with interleukin-1 specific receptor antagonist (IL-1Ra) ameliorates the deficits in memory (Frank et al., 2010) and L-LTP (Chapman et al., 2010).

It is not clear how aberrantly elevated levels of IL-1β in the hippocampus may produce limited, selective impairments in long-lasting forms of synaptic plasticity and memory. However, one intriguing possibility is suggested by the observation that infusion of IL-1β into the hippocampus decreases its capacity for transcription of brain-derived neurotrophic factor (BDNF) (Barrientos et al., 2004), and infusion of IL-1Ra protects it (Barrientos et al., 2003). BDNF plays a critical role in forms of long-lasting synaptic plasticity thought to be associated with consolidation of hippocampus-dependent memory (Tyler et al., 2002; Chao, 2003; Lu, 2003; Bramham and Messaoudi, 2005).

BDNF is synthesized as a precursor protein proBDNF that is post-translationally cleaved to produce mature BDNF (mBDNF). This processing of the BDNF protein appears to play a key role in determining its cellular functions (Barker, 2009; Greenberg et al., 2009). ProBDNF binds preferentially to the pan-neurotrophin receptor p75NTR, activates apoptosis-related signaling pathways, and may facilitate long-term depression in the hippocampus. In contrast, cleaved mBDNF binds to TrkB tyrosine kinase receptors, promotes cell survival, and facilitates some forms of long-term potentiation.

In the experiments presented here, we have examined the combined effects of aging and an infection on levels of pro- and mature BDNF protein isoforms and their receptors in the hippocampus. The infection appears to produce limited, relatively subtle synaptic deficits rather than large-scale, non-specific disruptions in hippocampal function (Chapman et al., 2010), and there is increasing evidence that some important pro-plasticity effects of BDNF are exerted locally at synapses (Kang and Schuman, 1996; Schratt et al., 2004). We have therefore prepared hippocampal synaptoneurosomes, enriching for peri-synaptic proteins, and increasing the probability of detecting subtle changes in proteins at synaptic sites.

Materials and Methods

Animals

The rats used were 3- and 24-month old male Fischer344/Brown Norway F1 crosses from the NIA Aged Rodent Colony. Animals were pair housed, on a 12-hr light dark cycle, with ad libitum access to food and water. Upon arrival, rats were allowed to acclimate to the animal facility for two weeks before experiments were begun. All experiments conformed to protocols approved by the University of Colorado Animal Care and Use Committee.

E. coli Infection Model

Stock E. coli cultures (ATCC 15746; American Type Culture Collection, Manassas, VA) were thawed and cultured overnight in 40mL of brain-heart infusion (BHI; DIFCO Laboratories, Detroit, MI) in an incubator (37 °C, 95% air + 5% CO2). The bacterial content in individual cultures was quantified by extrapolating from previously determined growth curves. Cultures were centrifuged for 15 min at 3000 rpm, the supernatants were discarded, and the bacteria were resuspended in sterile phosphate buffered saline (PBS), yielding a final dose of 2.5 × 10 9 CFU in 250μl. All animals received an intraperitoneal injection of 250μl of either E. coli or the vehicle (sterile PBS).

Blocking CNS Consequences of the Peripheral Infection

IL-1Ra was injected into the cisterna magna, rather than into the cerebral ventricles or the hippocampus, because this procedure doesn’t require surgery (which can itself produce memory impairments in aging animals). Rats were briefly anesthetized with halothane. The dorsal aspect of the skull was shaved and swabbed with 70% EtOH; then a 27-gauge needle attached via PE50 tubing to a 25 μl Hamilton syringe was inserted into the cisterna magna. The IL-1Ra (112 μg; Amgen, Thousand Oaks, CA) was administered i.c.m. in a total volume of 3 μl; and the animals received an i.p. injection of either E. coli or vehicle immediately after.

Synaptoneurosome Preparation

All tissue was collected 5 days after the injections. This time point was selected because: (1) all of the animals have completely recovered from the acute infection (E.g. fever has subsided) (Barrientos et al., 2009a); (2) the aging, but not the young E. coli-injected rats show significant impairments in long-term memory (Barrientos et al., 2006) and L-LTP (Chapman et al., 2010); and (3) levels of IL-1 protein in the hippocampus are still significantly elevated in the aging rats, but not in the young rats (Barrientos et al., 2009b).

Rats underwent rapid decapitation and hippocampi were extracted. Tissue was minced in 500μL homogenation buffer (HB) with protease inhibitors (1M Tris, 1M Sucrose, 0.5M EDTA, 0.25M EGTA, 0.5M NaF, 1M benzamidine, 100mM AEBSF) and homogenized using a glass tissue grinder with a Teflon pestle. Nuclear material and unbroken cells were removed by centrifugation at 960 × g for 15 minutes. The remaining supernatant was centrifuged at 10,000 × g for 15 minutes yielding an S2 cytosolic fraction and a P2 crude synaptoneurosomal fraction containing both pre- and post-synaptic material. The P2 synaptoneurosomal pellet was washed gently in 100μL of HB to remove sucrose and remaining HB. The P2 pellet was then homogenized using a 0.5mL plastic pestle in 100μL HB with 10μL of 10xSTE (1x final concentration) and sonicated. The P2 fraction obtained using this protocol is enriched for peri-synaptic components including pre- and post-synaptic proteins, terminal mitochondria and cytoplasm and synaptic vesicles (Booth and Clark, 1978; Whittaker, 1993). Synaptic enrichment of the P2 fraction was confirmed using synaptophysin and post-synaptic density 95 (PSD95), common synaptic markers. Protein content was quantified using the BCA protein assay (BioRad, Hercules, CA, USA).

Western Blots

Samples were prepared under reducing conditions in 4x Laemmli buffer and heated at 70°C for 10 minutes. For Western blotting, 40μg of protein sample were loaded onto 4–12% NuPage (Invitrogen) Bis-Tris SDS-polyacrylamide gels and transferred onto polyvinylidene fluoride membranes (Millipore, Billerica, MA, USA). Membranes were blocked in 5% milk/PBST for 30 minutes at room temperature; all primary antibody incubations were at 4°C overnight followed by 3 × 10 minute washes with PBST (phosphate buffered saline with Triton); secondary antibody incubations were at room temperature for 1 hour and washed 3 × 10 minutes. The following primary antibodies (and dilutions) were used: matureBDNF (1:1000; sc-546; Santa Cruz Biotechnology, Santa Cruz, CA, USA), proBDNF (1:500; ab72440; Abcam, Cambridge, MA, USA), pTrkB (1:700; pTrkBY816 antisera gift of Moses Chao, New York University School of Medicine) and total TrkB (1:1000; sc-8316; Santa Cruz Biotechnology, Santa Cruz, CA, USA), p75 (1:500; gift of Mark Bothwell, University of Washington, Seattle, WA), pPLCγ1 (1:1000; 07-2134) and total (phosphorylated and unphosphorylated) PLCγ1 (1:500; 05-366; Millipore, Temecula, CA, USA), pERK (1:1000; 9101) and total ERK (1:1000; 9102; Cell Signaling), and pAKT (1:1000; 4058) and total AKT (1:1000; 9272; Cell Signaling, Danvers, MA, USA). Blots were probed with synaptic markers synaptophysin (1:1000; sc-12737; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and PSD95 (1:1000; United Biomedical Inc., Hauppauge, NY, USA) to validate synaptoneurosome fractions, and β-tubulin (1:100,000; MAB1637; Chemicon, Temecula, CA, USA) and β-actin (1:5000; sc-47778; Santa Cruz Biotechnology, Santa Cruz, CA, USA) as loading controls. Identity of the BDNF isoform bands in synaptoneurosomes was confirmed by comparison with extracts from HeLa cells transfected with a plasmid that overexpresses BDNF, producing both the pro- and mature form. Secondary antibodies were purchased from GE Healthcare (Buckinghampshire, UK) and BioRad (Hercules, CA, USA) and diluted in the range of 1:5000 to 1:10000; SuperSignal West Pico Chemiluminescent was purchased from Pierce (Rockford, IL, USA). Following chemiluminescent application, blots were exposed to autoradiography film (Denville Scientific, St. Louis, MO, USA). Blots were stripped using Restore Western Blot Stripping Buffer (Pierce) for 15 minutes and washed 3 × 10 minutes in PBST and subjected to standard Western blotting conditions.

Analysis

Protein bands were quantified using ImageJ (NIH), and all bands were normalized to their actin controls. Because we had previously shown that the combination of age and infection uniquely disrupts BDNF-dependent plasticity and memory, we hypothesized that it might also uniquely reduce BDNF (and related proteins). We therefore used an unpaired t-test to determine if the level of the protein of interest in the aged + E. coli group differed from the level of the protein in the other groups. The p-value listed for each protein (or phosphorylation state ratio) is for an unpaired t-test comparing the mean of the aging + E. coli group to the mean of the summed values of the other test groups.

Results

Levels of the mature BDNF protein isoform are significantly reduced in hippocampal synaptoneurosomes prepared from aged animals with a recent history of infection

We hypothesized that aging and a recent history of infection might interact to disrupt biosynthesis or processing of BDNF protein in the hippocampus, decreasing the availability of BDNF for plasticity-related processes at synaptic sites. To begin investigating this possibility, we prepared synaptoneurosomes from hippocampi collected from young and aging rats 5 days after a vehicle or E. coli injection. This procedure produces a significant enrichment in synaptic proteins, making it possible to identify subtle experience-dependent changes in the protein composition of synapses (Whittaker, 1993).

Western blot analysis detected a specific proBDNF signal (ab72440 antibody, Abcam) in the 30–35 kDa range (Fig. 1B). The combination of age and infection produced a trend towards a slight (10–15%) reduction in the proBDNF signal but it did not reach significance t(18) = 1.234, p = 0.232. In contrast, further analysis with an antibody for the mature domain of BDNF (sc-546 antibody; Santa Cruz Biotechnology) (Lee et al., 2001) revealed that age and infection together reduced levels of mBDNF by more than half t(22) = 2.615, p = 0.0158 (Fig. 1C).

Figure 1.

Figure 1

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Infection differentially affects BDNF protein isoforms in aged vs. young animals. Western blot analysis showing enrichment of synaptic material in synaptoneurosomes, and levels of pro- and mature BDNF in hippocampal synaptoneurosomes prepared from young and aged rats, with and without a recent history of infection. (A) Representative examples of blots probed with a PSD95 antibody to confirm enrichment of synaptic material in the synaptoneurosomal (P2) vs. the cytosolic (S2) fractions. (B) Levels of proBDNF were not significantly reduced by the combination of aging and infection. (C) Infection markedly reduced mature BDNF in synaptic fractions from aged animals. Band intensities were quantified (NIH-ImageJ), normalized to actin controls, and expressed as percentages of mean protein levels from young vehicle-injected rats. Error bars indicate SEM. All graphs (here and below) represent a minimum of three independent experiments with 1–2 animals per group in each experiment. Asterisks indicate statistical significance from all other groups; individual P-values are reported in the text.

Levels of receptors for BDNF are not significantly altered by aging or a history of infection

In contrast to its effects on BDNF protein, the combination of age and infection produced no detectable changes in levels of BDNF receptors in hippocampal synaptoneurosomes prepared 5 days after the initial E. coli injection. Expression of the p75NTR receptor was unchanged (antibody gift of Mark Bothwell) (Fig. 2B). Similarly, total levels of TrkB did not vary significantly across conditions, nor was there a shift in the relative proportions of full-length vs. truncated (lacking the tyrosine kinase) TrkB receptor isoforms (sc-8316; Santa Cruz Biotechnology) (Fig. 2A).

Figure 2.

Figure 2

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Age and infection do not alter levels of BDNF receptors under the conditions of the study. Western blot analysis was performed on hippocampal synaptoneurosomes prepared from young and aged rats, with and without a recent history of infection. Levels of the (A) pan neurotrophin receptor p75NTR, and (B) principal TrkB receptor isoforms were unchanged. Quantification was as above.

Age and infection interact to reduce activation of TrkB and downstream signaling systems

Activation of TrkB by mBDNF triggers a series of phosphorylation events, beginning with the receptor, which can activate proteins in the three major growth factor–regulated signaling pathways: the phospholipase C-gamma1 (PLCγ1) pathway, the Ras/ERK pathway, and the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway (Greene and Kaplan, 1995; Huang and Reichardt, 2003). We found that the ratio of phospho-TrkB (antisera gift of Moses Chao) to total TrkB (sc-8316; Santa Cruz Biotechnology) was significantly reduced by the combination of age and infection, t(14) = 4.680, p = 0.0004 (Fig 3A). We next asked whether this was associated with reduced activation of PLCγ1, ERK and or Akt. We found that the ratio of phospho-PLC-γ1 (07-2134; Millipore) to total PLC-γ1 (05-366; Millipore) was significantly reduced in synaptoneurosomes from aged rats following infection, t(10) = 4.468, p = 0.0012 (Fig. 3B). This was also true of the ratio of phospho-ERK (9101; Cell Signaling) to total ERK (9102; Cell Signaling), t(10) = 5.581, p = 0.0002 (Fig. 3C). In contrast, we found that the ratio of phospho-Akt to total Akt was not significantly reduced under the conditions examined, t(10) < 1, p = 0.6568 (Fig. 3D).

Figure 3.

Figure 3

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Aging and infection reduce activation of TrkB and downstream activity in major TrkB-signaling pathways. Levels of phosphorylated TrkB (A), PLC-γ1 (B), and ERK (C) were significantly lower in synaptoneurosomes prepared from aged animals 5 days following infection; levels of phosho-Akt (D) were not. Quantification was as above.

Central administration of the anti-inflammatory cytokine IL-1Ra ameliorates the infection-induced reductions in mBDNF and activated-TrkB in synaptoneurosomes from aged rats

IL-1β is a major mediator of inflammatory responses in the brain as well as in the periphery. We have previously shown that blocking the actions of IL-1β in the brain, by injecting IL-1Ra into the cisterna magna at the time of the i.p. E. coli injection, blocks infection-evoked deficits in long-term synaptic plasticity and memory in aged rats (Chapman et al., 2010; Frank et al., 2010). Here we report that administration of IL-1Ra also blocks E. coli-evoked reductions in mBDNF, t(10) = 0.3511, p = 0.7328 (Fig. 4A) and phospho-TrkB, t(10) = 1.339, p = 0.2102 (Fig. 4B).

Figure 4.

Figure 4

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Blocking IL-1β signaling in the CNS blocks the E. coli-evoked reduction in synaptic levels of mBDNF protein (A) and phospo-TrkB in aged rats (B). E. coli injected rats received a concurrent injection of the anti-inflammatory cytokine IL-1Ra or vehicle into the cisterna magna. Hippocampi were collected, and synaptoneurosomes prepared 5 days after the injections. Quantification was as above.

Discussion

We have previously demonstrated that a peripheral immune challenge produces profound disruptions in forms of hippocampus-dependant long-term memory and synaptic plasticity known to be BDNF-dependent in aged, but not young F344xBN rats (Barrientos et al., 2006; Chapman et al., 2010). Here, we have extended these observations, examining for the first time the combined effects of aging and infection on levels of BDNF protein isoforms and their receptors at synaptic sites in the hippocampus. Our key findings are that an immune challenge in aging rats (1) triggered a minimal reduction in proBDNF and a much larger reduction in mature BDNF detectable in hippocampal synaptoneuosomes prepared 5 days after the injections, after all the rats had recovered from the acute infection, (2) had no significant effects on levels of BDNF receptors, but (3) significantly reduced phosphorylation of TrkB, and downstream activation of PLCγ1 and ERK - consistent with decreased availability of mBDNF for activation of TrkB, and (4) no longer reduced mBDNF and phospho-TrkB if IL-1 receptors in the brain were blocked with a selective antagonist.

These new data are consistent with the hypothesis that the interaction of aging and an infection might decrease availability of BDNF at hippocampal synapses, and thus might contribute to selective deficits in forms of long-lasting plasticity and memory that require BDNF for their full expression. We found that the interaction of aging and infection reduced levels of mBDNF at synaptic sites by more than fifty percent. Mouse models of BDNF haploinsufficiency have provided evidence that a critical threshold level of BDNF is necessary for full function in memory-related plasticity. Heterozygous BDNF (+/−) mice with approximately half the normal levels of BDNF in their brains have significant impairments in long-lasting synaptic plasticity (Korte et al., 1995; Patterson et al., 1996; Pang et al., 2004) and in hippocampus-dependent learning and memory (Linnarsson et al., 1997).

The consequences of reduction of BDNF protein isoforms are not yet so well studied, but mBDNF appears to play an important role in some forms of long-lasting synaptic plasticity in the hippocampus. Mature BDNF can be generated by cleavage of proBDNF by plasmin - an extracellular protease activated by tissue plasminogen activator (tPA)-dependent cleavage of plasminogen (Pang et al., 2004). Theta burst stimulation is reported to induce secretion tPA, and to increase extracellular conversion of proBDNF to mBDNF in cultures of hippocampal neurons (Nagappan et al., 2009). Application of mBDNF, but not a cleavage-resistant proBDNF, can rescue deficits in theta burst L-LTP hippocampal slices from mice lacking tPA or plasminogen (Pang et al., 2004). Mature BDNF can also rescue the impairment of theta–burst L-LTP caused by inhibition of protein synthesis in wild-type mice (Pang et al., 2004) - suggesting that the mBDNF isoform may be one of the proteins whose production is required for long-lasting enhancement of synaptic efficacy. There is now some corresponding evidence that production of adequate amounts of mBDNF may be important for hippocampus-dependent memory. A recent study indicates that increased cleavage of precursor proBDNF in the hippocampus is positively correlated with acquisition of contextual fear memory, while decreased cleavage is associated with extinction (Barnes and Thomas, 2008).

The effects of aging on BDNF mRNA and protein have been extensively studied and generally found to be modest (Pang and Lu, 2004). However, a few studies have now examined the impact of aging on BDNF protein isoforms. Aged Wistar rats with memory impairments are reported to have lower levels of total BDNF, but higher ratios of proBDNF to mBDNF than controls from a related strain known to have better preservation of cognitive function (Silhol et al., 2008). Perhaps not surprisingly, training in a spatial learning task increased levels of proBDNF in both young and aged Wistar rats, but only the young rats showed a corresponding increase in mBDNF (Silhol et al., 2007).

Several studies have examined the effects of immune challenge or proinflamatory cytokines on BDNF in the brain. Lipopolysaccharide (LPS) is a component of the cell wall of Gram-negative bacteria. A potent endotoxin, it leads to the release of pro-inflammatory cytokines such as IL-1β and TNF-α (Drum and Oppemtom, 1989). BDNF mRNA in the principle neurons of the hippocampus was strongly down-regulated 4 hours after an i.p. injection of LPS or IL-1β (Lapchak et al., 1993). Depolarization-induced release of BDNF from slices of dentate gyrus was not altered by administration of LPS several days earlier (Shaw et al., 2001). However, when levels of BDNF protein were examined 7 hrs after i.p. injection of LPS, LPS was found to produce a dose-dependent reduction in BDNF in the cortex and hippocampus (Guan and Fang, 2006).

Much less is known about the effects of immune challenge on BDNF protein isoforms, but i.p. injection of a single very high dose of LPS (3mg/kg) is reported to produce a small (approx. 15%) reduction in both proBDNF and mature BDNF in crude synaptoneurosomes prepared from the brains of young mice 3 days after the injection (Schnydrig et al., 2007). We have previously shown that a peripheral E. coli infection produces an exaggerated inflammatory response in the brains of aging animals, paralleled by specific deficits in forms of long-term memory and synaptic plasticity known to be strongly dependent on BDNF (Barrientos et al., 2009a; Barrientos et al., 2009b; Chapman et al., 2010). We now report that this inflammation also gives rise to a large reduction in mBDNF and TrkB signaling at synapses in the hippocampus.

It is not yet clear how exaggerated CNS inflammation may impact levels of BDNF protein isoforms. The precise circumstances and sites of BDNF production, processing and release, and the stability of the resulting isoforms is currently a very active, complex and controversy filled area of investigation (Barker, 2009) – and rather beyond the scope of this initial report. However, the work presented here provides new insights into naturalistic events that can affect BDNF production and processing in vivo and should provide a basis for further investigation of the interactions of aging, inflammation, and BDNF biology.

Acknowledgments

This work was supported by an Innovative Seed Grant Award from the University of Colorado (to SLP) and National Institute on Aging Grants 1R21AG031467 (to SLP), and 1R01AG02827 (to RMB and SFM). We thank R.K. Bachtell, T.R. Chapman, G.H. McClelland, and M.J. LaVoie for helpful discussions.

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