Regional differences in hippocampal PKA immunoreactivity after training and reversal training in a spatial Y‐maze task

Abstract

Citation for published version (APA): Havekes, R., Timmer, M., & Van der Zee, E. A. (2007). Regional differences in hippocampal PKA immunoreactivity after training and reversal training in a spatial Y-maze task. Hippocampus, 17(5), 338-348. https://doi.org/10.1002/hipo.20272 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. It is suggested that the hippocampus functions as a comparator by making a comparison between the internal representation and actual sensory information from the environment (for instance, comparing a previously learned location of a food reward with an actual novel location of a food reward in a Y-maze). However, it remains unclear to what extent the various hippocampal regions contribute to this comparator function. One of the proteins known to be crucially involved in the formation of hippocampus-dependent long-term memory is the adenosine 3 0 ,5 0 cyclic monophosphate dependent protein kinase (PKA). Here, we examined region-specific changes in immunoreactivity (ir) of the regulatory IIa,b subunits of PKA (PKA RIIa,b-ir) in the hippocampus during various stages of spatial learning in a Y-maze reference task. Thereafter, we compared changes in hippocampal PKA RIIa,b-ir induced by training and reversal training in which the food reward was relocated to the previously unrewarded arm. We show that: (1) There was a clear correlation between behavioral performance and elevated PKA RIIa,b-ir during the acquisition phase of both training and reversal training in area CA3 and dentate gyrus (DG), (2) PKA RIIa,b-ir was similarly enhanced in area CA1 during the acquisition phase of reversal training, but did not correlate with behavioral performance, (3) PKA RIIa,b-ir did not change during training or reversal training in the subiculum (SUB), (4) No changes in PKA RIIa,b protein levels were found using Western blotting, and (5) AMPA receptor phosphorylation at serine 845 (S845p; the PKA site on the glutamate receptor 1 subunit (GluR1)), was enhanced selectively during the acquisition phase of reversal training. These findings reveal that training and reversal training induce region-specific changes in hippocampal PKA RIIa,b-ir and suggest a differential involvement of hippocampal subregions in match-mismatch detection in case of Y-maze reference learning. Alterations in AMPA receptor regulation at the S845 site seems specifically related to the novelty detector function of the hippocampus important for match...

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

“…Alterations in GluA1 pS845 levels are known to affect behaviors, and transgenic mice expression a nonphosphorylatable mutant of GluA1, S845A, have altered learning and memory (Lee et al 2003;Havekes et al 2007;Clem and Huganir 2010). In this study, we demonstrate that GluA1 phosphorylation levels differed in various regions in the cGKII KO brain, and behaviors dependent on those brain regions were correspondingly altered in KO animals.…”

“…In addition, there are regional differences in kinase regulation, including regulation by PKA and ERK (Ortiz et al 1995;Havekes et al 2007). However, the molecular mechanism of such specificity is not clear.…”

“…Distinct regulation of phosphatases in the PFC and hippocampus leads to heterogeneity of GluA1-pS845 in the KO In order to investigate the mechanism that underlies the different levels of GluA1-pS845, we focused on the regionspecific control of phosphatases in the hippocampus and PFC although it has been proposed that there are regional differences in kinase regulation and expression (Ortiz et al 1995;de Vente et al 2001;Mazzucchelli et al 2002;Havekes et al 2007). Two different phosphatases are known to dephosphorylate GluA1-pS845, calcineurin and protein phosphatase 1 (PP1) (Lee et al 1998(Lee et al , 2000.…”

“…Phosphorylation of serine 845 of GluA1 (GluA1-pS845) is important for activity-dependent trafficking of GluA1-containing AMPARs and increases the level of extrasynaptic receptors (Roche et al 1996;Malinow and Malenka 2002;Derkach et al 2007;Serulle et al 2007;Shepherd and Huganir 2007). Behavioral studies of learning and memory show a contribution of GluA1-pS845 and experimental manipulations that prevent the phosphorylation of GluA1-pS845 have detrimental effects on learning and memory behaviors (Lee et al 2003;Havekes et al 2007;Clem and Huganir 2010). cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase II (cGKII) can mediate this phosphorylation (Derkach et al 2007;Serulle et al 2007).…”

Rat hippocampal theta rhythm during sensory mismatch

“…Recent studies suggest that that the HF could work as a comparator to detect changes (i.e., mismatch) between the internal representation and actual sensory information from the environment to encode new information (Hasselmo and Schnell, 1994;Hasselmo and Wyble, 1997;Moser and Paulsen, 2001;Havekes and Timmer, 2007). This further suggests that the HF should hold internal representation of the environmental information to be compared with incoming information (Gray, 1982;Vinogradova, 2001; Kumaran and Maguire, 2007).…”