Elsevier

Neurobiology of Aging

Volume 33, Issue 4, April 2012, Pages 832.e1-832.e14
Neurobiology of Aging

Abstract of online article
Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus

https://doi.org/10.1016/j.neurobiolaging.2011.07.015Get rights and content

Abstract

Aging increases the likelihood of cognitive decline after negative life events such as infection or injury. We have modeled this increased vulnerability in aged (24-month-old), but otherwise unimpaired F344xBN rats. In these animals, but not in younger (3-month-old) counterparts, a single intraperitoneal injection of E. coli leads to specific deficits in long-term memory and long-lasting synaptic plasticity in hippocampal area CA1—processes strongly dependent on brain-derived neurotrophic factor (BDNF). Here we have investigated the effects of age and infection on basal and fear-conditioning-stimulated expression of Bdnf in hippocampus. We performed in situ hybridization with 6 probes recognizing: total (pan-)BDNF mRNA, the 4 predominant 5′ exon-specific transcripts (I, II, IV, and VI), and BDNF mRNAs with a long 3′ untranslated region (3′ UTR). In CA1, aging reduced basal levels and fear-conditioning-induced expression of total BDNF mRNA, exon IV-specific transcripts, and transcripts with long 3′ UTRs; effects of infection were similar and sometimes compounded the effects of aging. In CA3, aging reduced all of the transcripts to some degree; infection had no effect. Effects in dentate were minimal. Northern blot analysis confirmed an aging-associated loss of total BDNF mRNA in areas CA1 and CA3, and revealed a parallel, preferential loss of BDNF mRNA transcripts with long 3′ UTRs.

Introduction

Cognitive deficits, particularly those related to learning and memory, are emerging as one of the major disorders of aging (Bishop et al., 2010). Although it is not clear that these deficits are a normal feature of aging—some older individuals retain a very high level of cognitive function—their incidence continues to increase with increasing age. This occurs in part because aging renders the brain more vulnerable to a variety of physiological and psychological stressors (Bekker and Weeks, 2003, VonDras et al., 2005, Wofford et al., 1996). Because relatively little is known about the mechanisms that underlie aging-associated increases in cognitive vulnerability, we have developed a rodent model to study them (Barrientos et al., 2006).

As we have previously reported, the cognitive abilities of aging (24-month-old) F344xBN rats appear comparable to those of their younger (3-month-old) counterparts, however, they are much more vulnerable to the consequences of a peripheral immune challenge (an intraperitoneal [i.p.] injection of live E. coli). Four days after the injection—after recovering from the active infection—the aging, but not the young rats show deficits in contextual fear conditioning, a hippocampus-dependent long-term memory task (Barrientos et al., 2006), and in theta burst-evoked, late-phase long-term potentiation (L-LTP) in the CA1 region of the hippocampus (Chapman et al., 2010), a form of long-lasting synaptic plasticity thought to be associated with consolidation of some spatial and/or contextual memories. These deficits are intriguingly specific. The infection does not compromise initial learning or formation of short-term memories, nor does it disrupt basal synaptic function or short-term synaptic plasticity in animals of either age. Together, these results suggest that age and a secondary immune challenge might selectively interfere with production of molecular substrates necessary for consolidation of memory-related synaptic plasticity without affecting more basic neuronal and synaptic functions.

In this study we investigated the impact of aging and infection on transcription of brain-derived neurotrophic factor (BDNF), a molecule that has been shown to be important for consolidation of hippocampus-dependent memory, and for theta burst evoked L-LTP (Bramham and Messaoudi, 2005, Lu et al., 2005, Tyler et al., 2002). The transcriptional organization of the BDNF gene is complex. At least 8 differentially regulated promoters give rise to multiple mRNA transcripts—each of which contains a distinct 5′ exon spliced to a common 3′ coding exon, and all of which encode an identical BDNF protein (Aid et al., 2007). Some of these promoters are strongly regulated by Ca+2-responsive transcription factors, like CREB, CaRF, and MeCP2 (Chen et al., 2003, Hong et al., 2008, Tao et al., 1998, Tao et al., 2002, West, 2008), and are activated in the hippocampus by behaviorally relevant stimuli like fear conditioning (Lubin et al., 2008, Rattiner et al., 2004). The functional significance of the different BDNF mRNA transcripts is not yet understood, but the different exons within these transcripts may help to orchestrate not only when BDNF can be made, but also for how long, and where in the cell (Righi et al., 2000, Tongiorgi et al., 1997). In addition, regardless of which promoter is activated, the gene uses 2 alternative polyadenylation sites, leading to mRNAs with either short or long 3′ unstranslated regions (UTRs). Recent data suggest that the BDNF mRNAs with the short 3′ UTRs are restricted to the cell body, whereas those with the long 3′ UTRs are also trafficked to dendrites (An et al., 2008). Thus, the BDNF gene can create at least 18 different mRNA transcripts with distinct 5′ and 3′ exons that might differently contribute to synaptic plasticity and memory consolidation.

Although activity-dependent BDNF transcription and trafficking has been repeatedly linked to physiological events like fear conditioning (Lubin et al., 2008, Rattiner et al., 2004), seizures (Kokaia et al., 1994, Lauterborn et al., 1996), and ischemia (Kokaia et al., 1995), very little is known about how expression of specific transcripts might be affected by aging and or infection. In the study presented here, we have used in situ hybridization to examine the impact of a peripheral immune challenge on expression of specific BDNF transcripts in the hippocampal subfields of young and aged rats in the basal state, and 1 hour after contextual fear conditioning. In addition, we performed Northern blot analysis to investigate the possibility that age and/or infection might differentially affect levels of transcripts with short or long 3′ UTRs.

Section snippets

Animals

Rats were 3- and 24-month-old male Fisher344/Brown Norway F1 hybrids from the NIA Aged Rodent Colony. They were allowed to acclimate to the animal facility for at least 2 weeks before experiments began. The animals were pair housed, on a 12-hour light dark cycle, with ad libitum access to food and water. All experiments were conducted in accordance with protocols approved by the University of Colorado Animal Care and Use Committee.

E. coli infection

Stock E. coli cultures (ATCC 15746; American Type Culture

Total (pan-)BDNF mRNA

We have previously demonstrated that the combination of aging and a recent history of infection gives rise to specific deficits in forms of memory and memory-related synaptic plasticity (Barrientos et al., 2006, Chapman et al., 2010) known to be strongly dependent on BDNF (Bramham and Messaoudi, 2005, Chao, 2003, Lu, 2003, Schinder and Poo, 2000, Tyler et al., 2002). We began the studies described here by asking if these deficits could be correlated with changes in total BDNF gene expression in

Discussion

We have previously demonstrated that in 24-month-old, but not in 3-month-old F344xBN rats, a single i.p. injection of E. coli leads to specific deficits in forms of long-term memory and long-lasting synaptic plasticity in hippocampal area CA1 (Barrientos et al., 2006, Chapman et al., 2010) that are known to be strongly dependent on BDNF (Bramham and Messaoudi, 2005, Lu et al., 2005, Tyler et al., 2002). The studies described here extend these observations, investigating the possibility that the

Disclosure statement

None of the authors have actual or potential conflicts of interest related to the work reported here.

All experiments were conducted in accordance with protocols approved by the University of Colorado Animal Care and Use Committee.

Acknowledgements

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 SFM).

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