Abstract
Traumatic brain injury (TBI) results in significant impairments in hippocampal synaptic plasticity. A molecule critically involved in hippocampal synaptic plasticity, 3′,5′-cyclic adenosine monophosphate, is downregulated in the hippocampus after TBI, but the mechanism that underlies this decrease is unknown. To address this question, we determined whether phosphodiesterase (PDE) expression in the hippocampus is altered by TBI. Young adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. Animals were analyzed by western blotting for changes in PDE expression levels in the hippocampus. We found that PDE1A levels were significantly increased at 30 min, 1 h and 6 h after TBI. PDE4B2 and 4D2 were also significantly increased at 1, 6, and 24 h after TBI. Additionally, phosphorylation of PDE4A was significantly increased at 6 and 24 h after TBI. No significant changes were observed in levels of PDE1B, 1C, 3A, 8A, or 8B between 30 min to 7 days after TBI. To determine the spatial profile of these increases, we used immunohistochemistry and flow cytometry at 24 h after TBI. PDE1A and phospho-PDE4A localized to neuronal cell bodies. PDE4B2 was expressed in neuronal dendrites, microglia and infiltrating CD11b+ immune cells. PDE4D was predominantly found in microglia and infiltrating CD11b+ immune cells. To determine if inhibition of PDE4 would improve hippocampal synaptic plasticity deficits after TBI, we treated hippocampal slices with rolipram, a pan-PDE4 inhibitor. Rolipram partially rescued the depression in basal synaptic transmission and converted a decaying form of long-term potentiation (LTP) into long-lasting LTP. Overall, these results identify several possible PDE targets for reducing hippocampal synaptic plasticity deficits and improving cognitive function acutely after TBI.
Highlights
Every year in the United States an estimated 1.7 million people sustain a traumatic brain injury (TBI) and nearly 70–80% of those who survive report chronic learning and memory deficits (Lew et al, 2006; Faul et al, 2010)
We have previously reported that cyclic adenosine monophosphate (cAMP) levels are decreased in the hippocampus from 15 min to 4 h after Traumatic brain injury (TBI) (Atkins et al, 2007)
To determine whether this decrease is associated with changes in levels of PDE, the enzyme that degrades cAMP, we evaluated the hippocampus by western blot analysis for PDE expression
Summary
Every year in the United States an estimated 1.7 million people sustain a traumatic brain injury (TBI) and nearly 70–80% of those who survive report chronic learning and memory deficits (Lew et al, 2006; Faul et al, 2010). This progressive hippocampal atrophy is observed in experimental models of TBI, and is accompanied by a loss of dentate hilar cells and neurons in the CA3 region as well as synaptic loss (Maxwell et al, 2003; Hall et al, 2005; Scheff et al, 2005; Witgen et al, 2005). In addition to these gross morphological changes, in experimental models of TBI there are deficits in hippocampal basal synaptic transmission and longterm potentiation (LTP; Miyazaki et al, 1992; Titus et al, 2013b). Finding molecular targets to attenuate the damage caused by TBI and improve hippocampal synaptic plasticity is of critical importance to assist the estimated 3–5 million people currently living with cognitive disabilities from TBI in the United States (Langlois et al, 2006; Zaloshnja et al, 2008)
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