Human molecular geneticsAug 13, 2011

Higher PKA signaling may impair recognition and spatial memory in Huntington's disease

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 4, 2026

Abstract

Severe cognitive deficits were detected in the R6/1 mouse model of Huntington's disease before the onset of motor symptoms.

Hippocampal cAMP-dependent protein kinase (PKA) was hyper-activated in naïve R6/1 mice compared to wild-type mice.
Increased PKA activity led to hyper-phosphorylation of several substrates, including NMDA receptor subunit 1 and striatal-enriched protein tyrosine phosphatase.
Some phosphodiesterase 4 family members were found to be down-regulated in correlation with PKA over-activation.
Similar molecular changes were observed in the hippocampus of R6/2 mice and Huntington's disease patients.
Chronic treatment of wild-type mice with the PDE4 inhibitor rolipram induced learning and memory deficits akin to those in R6 mice.
Inhibition of hippocampal PKA by infusing Rp-cAMPS restored long-term memory in R6/2 mice.

Simplified

Huntington's disease (HD) patients and mouse models show learning and memory impairment even before the onset of motor symptoms. However, the molecular events involved in this cognitive decline are still poorly understood. Here, using three different paradigms, the novel object recognition test, the T-maze spontaneous alternation task and the Morris water maze, we detected severe cognitive deficits in the R6/1 mouse model of HD before the onset of motor symptoms. When we examined the putative molecular pathways involved in these alterations, we observed hippocampal cAMP-dependent protein kinase (PKA) hyper-activation in naïve R6/1 mice compared with wild-type (WT) mice, whereas extracellular signal-regulated kinase 1/2 and calcineurin activities were not modified. Increased PKA activity resulted in hyper-phosphorylation of its substrates N-methyl-D-aspartate receptor subunit 1, Ras-guanine nucleotide releasing factor-1 and striatal-enriched protein tyrosine phosphatase, but not cAMP-responsive element binding protein or the microtubule-associated protein tau. In correlation with the over-activation of the PKA pathway, we found a down-regulation of the protein levels of some phosphodiesterase (PDE) 4 family members. Similar molecular changes were found in the hippocampus of R6/2 mice and HD patients. Furthermore, chronic treatment of WT mice with the PDE4 inhibitor rolipram up-regulated PKA activity, and induced learning and memory deficits similar to those seen in R6 mice, but had no effect on R6/1 mice cognitive impairment. Importantly, hippocampal PKA inhibition by infusion of Rp-cAMPS restored long-term memory in R6/2 mice. Thus, our results suggest that occlusion of PKA-dependent processes is one of the molecular mechanisms underlying cognitive decline in R6 animals.

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Higher PKA signaling may impair recognition and spatial memory in Huntington's disease

Abstract

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