Increased PKA signaling disrupts recognition memory and spatial memory: role in Huntington's disease

Abstract

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.

Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

“…Colony maintenance resulted in a decrease of the CAG repeat length, in agreement with CAG repeat instability as previously described by other groups (41)(42)(43). Mouse genotype was determined as previously described (44). CAG repeat length was determined by PCR amplification of the repeat using HD1 and HD2 fluorescently labeled primers (45) and subsequent size determination in an ABI 3100 analyzer (Applied Biosystems).…”

Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

“…This cross talk between PKA and the proteasome might be brain area specific or disease stage dependent. In the hippocampus of an HD mouse model (R6/1), PKA was upregulated before the onset of motor impairment because of the downregulation of phosphodiesterase 4, which might have contributed to defects in recognition memory and spatial memory (35). Cell-type-specific regulation of Rpt subunits and UPS activity, probably due to differential structural changes in the proteasome in different tissues (5), might also account for this brain-area-specific regulation of PKA in HD.…”

PDE Inhibition and cognition enhancement

“…First, several of the PDE families have notably restricted distributions, including PDE10A, which is very highly expressed in striatal medium spiny neurons, PDE11, which shows particularly high expression levels in dorsal root ganglia, and PDE6, which is only expressed in retina. For PDE10A, localization has been an important clue and guide in directing the evaluation of PDE10A inhibitors for the treatment of schizophrenia [18] and Huntington's disease [19]. However, PDE10A is an exception, and the majority of PDEs are more broadly distributed.…”