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

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 cAMPPKA 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 exacerbation of cognitive impairments in aged animals with TBI may be due to decreased cAMP levels and deficits in hippocampal LTP.

Phosphodiesterase Inhibitors as Therapeutics for Traumatic Brain Injury

“…The upstream mechanisms that result in this decrease in basal CREB phosphorylation are still being delineated. We and others have shown that basal cAMP levels are not altered in the hippocampi of aged animals [19, 54]. However, there are suggestions that this decrease in basal CREB phosphorylation may be due to increased phosphatase activity since studies have reported age-related increases in phosphatase levels [52, 55].…”

“…Many intracellular signaling cascades are activated acutely following TBI, however, the cAMP-PKA signaling pathway is unusual in that this pathway is one of the few that is acutely depressed after TBI [18, 19]. Fluid-percussion brain injury, a brain injury model that results in both focal and diffuse injury within the brain, decreases levels of cAMP within both the injured cortex and hippocampus by 15 minutes after trauma.…”

“…The aforementioned changes were in reference to moderate brain injury severity. In contrast, mild fluid-percussion brain injury has no significant effect on cAMP levels within the hippocampus in young adult animals, although as discussed in Section 4, this does not hold true for aged animals [19]. In addition, cortical changes in cAMP after mild TBI are less significant than what is observed after moderate TBI and independent of age.…”

“…Given the well-known age-related changes in cAMP-mediated signaling in the aged brain, we examined changes in cAMP in aged animals as compared to young adult animals after both mild and moderate TBI [19]. We found that cAMP levels were altered in an injury severity-dependent manner (Fig.…”

Hippocampal cAMP/PKA/CREB is required for neuroprotective effect of acupuncture

“…The cAMP/PKA/cAMP response element binding protein (CREB) pathway has been shown to induce functional presynaptic boutons in the hippocampus [13]. Recent studies suggest that the inactivation of the cAMP/PKA/CREB pathway Physiology & Behavior 139 (2015) [482][483][484][485][486][487][488][489][490] probably causes pathological postischemic synaptic plasticity [14,15]. For example, the deficits in hippocampal LTP could be reversed by phosphodiesterase (PDE) inhibitors such as rolipram, which raises cAMP levels [16].…”