Age-dependent alterations in cAMP signaling contribute to synaptic plasticity deficits following traumatic brain injury
Graphical abstract
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.
References (59)
- et al.
Capabilities of the WinLTP data acquisition program extending beyond basic LTP experimental functions
J Neurosci Methods
(2007) - et al.
Effects of repeated administration of rolipram, a cAMP-specific phosphodiesterase inhibitor, on acetylcholinergic indices in the aged rat brain
Arch Gerontol Geriatr
(1993) - et al.
Modulation of the cAMP signaling pathway after traumatic brain injury
Exp Neurol
(2007) - et al.
Age-related decrease in the N-methyl-d-aspartateR-mediated excitatory postsynaptic potential in hippocampal region CA1
Neurobiol Aging
(1997) - et al.
Desipramine and noradrenergic neurotransmission in aging: failure to respond in aged laboratory animals
Neuropharmacology
(1987) - et al.
Age and neuroinflammation: a lifetime of psychoneuroimmune consequences
Neurol Clin
(2006) - et al.
Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus
Exp Neurol
(2005) - et al.
Middle age increases tissue vulnerability and impairs sensorimotor and cognitive recovery following traumatic brain injury in the rat
Behav Brain Res
(2004) - et al.
Differential changes of cAMP-dependent protein kinase activity and 3H-cAMP binding sites in rat hippocampus during maturation and aging
Neurosci Lett
(2001) - et al.
A non-radioactive assay for the cAMP-dependent protein kinase activity in rat brain homogenates and age-related changes in hippocampus and cortex
Brain Res
(2001)
Age-related disturbance of memory and CREB phosphorylation in CA1 area of hippocampus of rats
Brain Res
Increased cAMP immunostaining in cerebral vessels in Alzheimer’s disease
Brain Res
Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain
Brain Res
Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus
Neurobiol Aging
Age-related subsensitivity of cerebellar Purkinje neurons to locally applied beta 1-selective adrenergic agonist
Neurobiol Aging
Alteration of CREB phosphorylation and spatial memory deficits in aged 129T2/Sv mice
Neurobiol Aging
Behavioral, electrophysiological, and histopathological consequences of mild fluid-percussion injury in the rat
Brain Res
Differential expression of cytokines and chemokines during secondary neuron death following brain injury in old and young mice
Neurosci Lett
Molecular correlates of age-specific responses to traumatic brain injury in mice
Exp Gerontol
Oxidative stress in head trauma in aging
Free Radic Biol Med
Age-related changes in theta frequency stimulation-induced long-term potentiation
Neurobiol Aging
Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation
Neuroscience
Impaired expression of neuroprotective molecules in the HIF-1alpha pathway following traumatic brain injury in aged mice
J Neurotrauma
Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway
Proc Natl Acad Sci U S A
Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory
Proc Natl Acad Sci U S A
Long-term neurologic outcomes after traumatic brain injury
J Head Trauma Rehabil
Intracellular redox state alters NMDA receptor response during aging through Ca2+/calmodulin-dependent protein kinase II
J Neurosci
Potential adaptive function for altered long-term potentiation mechanisms in aging hippocampus
J Neurosci
Increased phosphorylation of the neuronal L-type Ca(2+) channel Ca(v)1.2 during aging
Proc Natl Acad Sci U S A
Cited by (38)
Aging, circadian disruption and neurodegeneration: Interesting interplay
2023, Experimental GerontologyComparative analysis of hippocampal transcriptional features between major depressive disorder patients and animal models
2021, Journal of Affective DisordersCitation Excerpt :Low regulatory expression of CREB was found in the postmortem hippocampus of patients with depression (Duric et al., 2010). Many lines of evidence have shown that the cAMP-dependent PKA/CREB signaling pathway is involved in the regulation of synaptic plasticity and learning and memory, and its disturbance can induce the neurologic cascade of depression, including abnormal regional brain activity, synaptic dysfunction and neurogenesis impairment (Esteban et al., 2003; Nguyen and Woo, 2003; Titus et al., 2013; Vitolo et al., 2002). PKA, as the upstream activator of CREB, has been shown to have an antidepressant effect by regulating CREB or p-CREB (Hu et al., 2012).
Alterations in cyclic nucleotide signaling are implicated in healthy aging and age-related pathologies of the brain
2021, Vitamins and HormonesCitation Excerpt :Coinciding with these results, age-related neurophysiological and memory deficits are effectively rescued in rodents by overexpression of CREB in the hippocampus (Ma et al., 2019; Marchese et al., 2017; Yu, Curlik, Oh, Yin, & Disterhoft, 2017). pCREB shows variable patterns in adult rodent cortex, with a notable age-related decrease in parietal regions (Titus et al., 2013) but an age-related upsurge in prefrontal cortical regions (Ramos et al., 2003; Vandesquille et al., 2013). Once more, age-related changes in cyclic nucleotide signaling prove to be brain region-specific, with decreased activity in hippocampus and some cortical regions, but upregulation in prefrontal cortex.
How do stupendous cannabinoids modulate memory processing via affecting neurotransmitter systems?
2021, Neuroscience and Biobehavioral Reviews