Elsevier

Neuroscience

Volume 231, 12 February 2013, Pages 182-194
Neuroscience

Age-dependent alterations in cAMP signaling contribute to synaptic plasticity deficits following traumatic brain injury

https://doi.org/10.1016/j.neuroscience.2012.12.002Get rights and content

Abstract

The elderly have comparatively worse cognitive impairments from traumatic brain injury (TBI) relative to younger adults, but the molecular mechanisms that underlie this exacerbation of cognitive deficits are unknown. Experimental models of TBI have demonstrated that the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway is downregulated after brain trauma. Since the cAMP-PKA signaling pathway is a key mediator of long-term memory formation, we investigated whether the TBI-induced decrease in cAMP levels is exacerbated in aged animals. Aged (19 months) and young adult (3 months) male Fischer 344 rats received sham surgery or mild (1.4–1.6 atmospheres, atm) or moderate (1.7–2.1 atm) parasagittal fluid-percussion brain injury. At various time points after surgery, the ipsilateral parietal cortex, hippocampus, and thalamus were assayed for cAMP levels. Mild TBI lowered cAMP levels in the hippocampus of aged, but not young adult animals. Moderate TBI lowered cAMP levels in the hippocampus and parietal cortex of both age groups. In the thalamus, cAMP levels were significantly lowered after moderate, but not mild TBI. To determine if the TBI-induced decreases in cAMP had physiological consequences in aged animals, hippocampal long-term potentiation (LTP) in the Schaffer collateral pathway of the CA1 region was assessed. LTP was significantly decreased in both young adult and aged animals after mild and moderate TBI as compared to sham surgery animals. Rolipram rescued the LTP deficits after mild TBI for young adult animals and caused a partial recovery for aged animals. However, rolipram did not rescue LTP deficits after moderate TBI in either young adult or aged animals. These results indicate that the exacerbation of cognitive impairments in aged animals with TBI may be due to decreased cAMP levels and deficits in hippocampal LTP.

Highlights

► Mild TBI decreased cAMP in the hippocampi of aged, but not young adult animals. ► Moderate TBI decreased cAMP in aged and young adult rats. ► A phosphodiesterase inhibitor rolipram rescued LTP deficits in young adult animals. ► Rolipram partially rescued LTP in aged animals after mild but not moderate TBI.

Introduction

The incidence of traumatic brain injury (TBI) is characterized by a tri-modal age distribution, with the highest incidence occurring in young children under the age of 5, young adults between 15 and 24 years of age, and in the elderly greater than 65 years (Faul et al., 2010). The numbers of elderly in the US are projected to increase by 42% between 2010 and 2050, with nearly one in five people aged 65 or older by 2030 (Vincent and Velkoff, 2010). Concurrently, the incidence in TBI has doubled in the past 18 years (Ramanathan et al., 2012). Age is one of the most important predictors of outcome after TBI since the ability to withstand brain injury diminishes with age. This is reflected in the fact that the highest rates of TBI-associated hospitalizations and death occur in the elderly even though the elderly are ranked as the third highest age group for TBI incidence (Susman et al., 2002, Stocchetti et al., 2012). Aged adults are more likely to remain severely disabled or vegetative after TBI as compared to young adults, and 91% of severe TBI patients older than 56 years suffer significant disability (Wilson et al., 1988, Stocchetti et al., 2012). Even a mild TBI that produces only a temporary cognitive impairment in a young adult can result in a significant, prolonged cognitive disability in an aged adult (Susman et al., 2002). TBI is an epigenetic risk factor for Alzheimer’s and Parkinson’s diseases, compounding recovery from TBI (Bazarian et al., 2009). This makes TBI a significant health problem in the elderly; one that is likely to grow as our population ages.

The progressive loss in the ability to handle stress and injury in aged adults has been recapitulated in experimental models of brain injury. Aged animals as compared to young adult animals exhibit more severe impairments in water maze performance and motor ability after TBI (Hamm et al., 1992, Maughan et al., 2000, Onyszchuk et al., 2008, Itoh et al., 2012). Even middle-aged rats in comparison to young adult rats have larger cortical lesions and severely impaired water maze performance after bilateral cortical contusion (Hoane et al., 2004). There have been some mechanistic studies to determine why injury-induced impairments are exacerbated in older animals. Previous studies have not detected any age-related differences in blood pressure, blood glucose levels, and weight loss, suggesting that the worsened pathology in aged animals after TBI is more likely caused by changes in biochemical signaling cascades rather than systemic complications due to age (Hamm et al., 1991, Hamm et al., 1992, Gilmer et al., 2010). Accordingly, higher toxic levels of calcium accumulation in hippocampal neurons occur after TBI and intracellular calcium levels return to basal levels more slowly in older animals (Osteen et al., 2001). Aged animals also have higher levels of pro-inflammatory cytokines such as interleukin-1β, tumor necrosis factor-α, and interleukin-6, increased oxidative damage, and decreased expression of neuroprotective genes after brain trauma (Sandhir et al., 2004, Shah et al., 2006, Shao et al., 2006, Onyszchuk et al., 2008, Anderson et al., 2009, Gilmer et al., 2010, Itoh et al., 2012). These studies indicate that several aspects of secondary injury mechanisms in TBI are aggravated with age.

There are significant age-related changes in cyclic AMP (cAMP)-mediated signaling in the non-injured brain and this may underlie some of the impairments seen in hippocampal synaptic plasticity and learning in the aged animal after TBI. cAMP is an important second messenger in activating several intracellular signaling pathways, including protein kinase A (PKA) which phosphorylates a key transcription factor required for long-term memory formation, cAMP response-element binding protein (CREB) (Waltereit and Weller, 2003). PKA activity and basal phosphorylation levels of CREB are lower in the hippocampi of aged rats as compared to young adult rats (Mons et al., 2004, Reis et al., 2005). Furthermore, CRE-binding activity is lower in memory-impaired aged animals (Karege et al., 2001a). This may be due to the depression of adenylyl cyclase activity or levels, as norepinephrine signaling through the β-adrenergic receptor is unable to fully stimulate adenylyl cyclase activity in the aged rat hippocampus (Bickford-Wimer et al., 1987, Parfitt and Bickford-Wimer, 1990, Mons et al., 2004).

These impairments in the cAMP-PKA pathway probably result in impaired synaptic plasticity. Aged animals have deficits in hippocampal long-term potentiation (LTP) that are reversed by phosphodiesterase inhibitors such as rolipram, which raises cAMP levels (Bach et al., 1999). Correspondingly, aged rats have hippocampal-dependent memory deficits that are ameliorated by rolipram administration (Bach et al., 1999). Furthermore, in an Alzheimer mouse model, transgenic mice expressing mutant β-APP and presenilin-1 proteins show improvements in hippocampal LTP and hippocampal-dependent learning with rolipram treatment (Gong et al., 2004). In our previous study, we found that cAMP levels are significantly decreased in young adult animals after TBI and that rolipram could rescue the decrease in cAMP levels (Atkins et al., 2007). Thus, we hypothesized that aged animals have a worse functional outcome after TBI due to a decrease in cAMP levels and that these deficits can be rescued with rolipram treatment.

Section snippets

Fluid-percussion brain injury surgery

All experimental procedures were in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals and approved by the University of Miami Institutional Animal Care and Use Committee. Animals were screened daily by in-house veterinarian technicians for health problems such as cataracts, jaundice, and tumors; only healthy animals were included in the study. Food and water intake was monitored and available ad libitum. Animals were singly housed and maintained

Basal cAMP levels and CREB phosphorylation in aged animals

The effects of age on basal cAMP levels and CREB phosphorylation were assessed by comparing aged (19 months) to young adult (3 months) Fischer 344 rats. The right parietal cortex, hippocampus and thalamus were assayed by ELISA for cAMP levels and by western blotting for CREB Ser133 phosphorylation and total CREB levels (Fig. 1). Basal cAMP levels were significantly higher in the parietal cortex of aged animals as compared to young adult animals, unchanged in the hippocampus, and significantly

Discussion

In this study, we investigated whether TBI exacerbates changes in cAMP in aged animals. We first determined if, in non-injured aged animals, the reported decrease in basal phospho-CREB correlated with decreased basal cAMP (Karege et al., 2001a, Hattiangady et al., 2005). Surprisingly, we observed a small, but significant increase in cAMP in the aged parietal cortex and no change in the hippocampus (Davare and Hell, 2003). The increase in cAMP in the parietal cortex may be indicative of

Conclusion

We have evidence to show that mild TBI lowers cAMP levels in the hippocampus more in aged animals as compared to young adult animals. Deficits in hippocampal LTP induced by mild TBI were rescued completely by rolipram in young adult animals, but only partially in aged animals. Rolipram did not significantly rescue deficits in LTP after moderate TBI in either age group, although there was a trend for a partial rescue in young adult animals. These studies indicate that therapies utilizing

Acknowledgments

The authors thank Dayaris Morffi for technical assistance and Drs. W. Dalton Dietrich, H.M. Bramlett, I. Hentall, and Kaming Lo for critical reading of the manuscript. We thank the University of Miami Biostatistics Collaboration and Consulting Core for statistical support. This work was supported by NIH Grants AG033266, NS069721, NS056072 and The Miami Project to Cure Paralysis.

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