MicelackingRas- GRF1 showcontextualfearcondition- ing butnotspatialmemoryimpair- ments:convergentevidencefromtwo independentlygeneratedmousemutant lines

Abstract

Ras-GRF1 is a neuronal specific guanine exchange factor that, once activated by both ionotropic and metabotropic neurotransmitter receptors, can stimulate Ras proteins, leading to long-term phosphorylation of downstream signaling. The two available reports on the behavior of two independently generated Ras-GRF1 deficient mouse lines provide contrasting evidence on the role of Ras-GRF1 in spatial memory and contextual fear conditioning. These discrepancies may be due to the distinct alterations introduced in the mouse genome by gene targeting in the two lines that could differentially affect expression of nearby genes located in the imprinted region containing the Ras-grf1 locus. In order to determine the real contribution of Ras-GRF1 to spatial memory we compared in Morris Water Maze learning Brambilla’s mice with a third mouse line (GENA53) in which a non-sense mutation was introduced in the Ras-GRF1 coding region without additional changes in the genome and we found that memory in this task is normal. Also, we measured both contextual and cued fear conditioning, which were previously reported to be affected in Brambilla’s mice, and we confirmed that contextual learning but not cued conditioning is impaired in both mouse lines. In addition, we also tested both lines for the first time in conditioned place aversion in the Intellicage, an ecological and remotely controlled behavioral test, and we observed normal learning. Finally, based on previous reports of other mutant lines suggesting that Ras-GRF1 may control body weight, we also measured this non-cognitive phenotype and we confirmed that both Ras-GRF1 deficient mutants are smaller than their control littermates. In conclusion, we demonstrate that Ras-GRF1 has no unique role in spatial memory while its function in contextual fear conditioning is likely to be due not only to its involvement in amygdala functions but possibly to some distinct hippocampal connections specific to contextual learning.

Spatial learning and long‐term memory impairments in RasGrf1 KO, Pttg1 KO, and double KO mice

“…Our data regarding RasGrf1 KO mice match those of d'Isa et al. (), which after years of controversy, demonstrated that RasGrf1 KO mice have no spatial memory defects (Table ), but impaired contextual fear conditioning. In particular, the report of d'Isa et al.…”

“…In particular, the report of d'Isa et al. (). used the GENA53 mouse line, in which a nonsense mutation was introduced in the RasGrf1 coding region without additional changes in the genome and explained the different spatial learning phenotype found between Giese et al.…”

Differential hippocampal gene expression is associated with climate‐related natural variation in memory and the hippocampus in food‐caching chickadees

“…; d'Isa et al . ), while overexpression of RasGRF1 results in memory‐enhancing effects in most behavioural tasks but not spatial learning (Fasano et al . ).…”

Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

“…This discrepancy can be reconciled since the spatial reference memory evaluated in the water or Barnes mazes is not associated with contextual fear memory [61,62] and each of these distinct types of memories might have different underlying mechanisms [63], following different biological functions and adaptive significance. It is also likely that the change in the salience of the conditioning context [64,65] or switching the context conditioning from background to foreground, by eliminating the delay component of tone presentation, might increase the sensitivity of the context testing paradigm in identifying the impairment of the CRND8 mice in this type of memory at earlier ages.…”