Novelty-induced memory consolidation is accompanied by increased Agap3 transcription: a cross-species study

Abstract

Novelty-induced memory consolidation is a well-established phenomenon that depends on the activation of a locus coeruleus-hippocampal circuit. It is associated with the expression of activity-dependent genes that may mediate initial or cellular memory consolidation. Several genes have been identified to date, however, to fully understand the mechanisms of memory consolidation, additional candidates must be identified. In this cross-species study, we used a contextual novelty-exploration paradigm to identify changes in gene expression in the dorsal hippocampus of both mice and rats. We found that changes in gene expression following contextual novelty varied between the two species, with 9 genes being upregulated in mice and 3 genes in rats. Comparison across species revealed that ArfGAP with a GTPase domain, an ankyrin repeat and PH domain 3 (Agap3) was the only gene being upregulated in both, suggesting a potentially conserved role for Agap3. AGAP3 is known to regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor trafficking in the synapse, which suggests that increased transcription of Agap3 may be involved in maintaining functional plasticity. While we identified several genes affected by contextual novelty exploration, we were unable to fully reverse these changes using SCH 23390, a dopamine D₁/D₅ receptor antagonist. Further research on the role of AGAP3 in novelty-induced memory consolidation could lead to better understanding of this process and guide future research.

Keywords: AGAP3; Behavioural tagging; Dopamine; Dopamine receptor antagonist; Hippocampus; Immediate-early gene; Locus coeruleus; Memory consolidation; Novelty; Synaptic tagging and capture hypothesis.

Fig. 1

Contextual novelty-induced gene expression in the dorsal hippocampus in mice and rats. (A) Behavioral equipment for contextual novelty in mice. (B) Schematic overview of the mouse experimental design. Animals were divided into two groups in the critical session (Group CC, caged control; Group NOV, 5-min contextual novelty exploration; n = 5 in each group). Brain samples were collected 25 min after a 5-min novelty exploration, followed by laser microdissection of the hippocampal CA1 pyramidal cell layer and multiplexed gene expression analysis. (C) Behavioral equipment for contextual novelty in rats. (D) Schematic overview of rat experimental design. Animals were divided into three groups in the critical session (Group CC, caged control; Group NOV-Veh, 5-min contextual novelty exploration with Veh injection; Group NOV-SCH, 5-min novelty exploration with SCH 23390 injection; n = 10 in each group). Brain samples were collected 30 min after a 5-min novelty exploration, followed by dissection of the dorsal hippocampus and multiplexed gene expression analysis

Fig. 2

Dopamine D₁/D₅ receptor-dependent novelty-induced enhancement of persistence of object location memory in rats. Graphs display the percentage of time spend exploring the object in the novel location, relative to the total object exploration time, during the first 2 min of both the encoding and the test trials. The dashed line represents the chance level. (A) A schematic of experimental design, along with the results from a 20-min encoding protocol, showing 1-h memory but not 24-h memory in behavioral batch 2. Welch’s t-test revealed a significant difference between 1-h (n = 18) and 24-h memory (n = 6) (68.10 ± 2.60% vs. 52.95 ± 6.73%; t₍₂₂₎ = 2.576, p = 0.017). Effect size calculations demonstrated an extremely high Hedges’ g-value (g = − 1.172; lower 95% confidence interval (CI) = − 2.117, upper CI = − 0.205). Preference during encoding was unaffected by the experimental setup (52.16 ± 1.78% vs. 46.99 ± 3.71%; t₍₂₂₎ = 1.160, p = 0.201). (B) A schematic of experimental design, along with the results showing the effects of contextual novelty exploration on 24-h memory in behavioral batch 3. Welch’s t-test indicated a significant increase in 24-h memory after contextual novelty exploration (n = 10) compared with controls (n = 10) (46.95 ± 3.71% vs. 64.73 ± 4.54%; t₍₁₈₎ = 3.035, p = 0.007). Effect size calculations revealed an extremely high Hedges’ g-value (g = 1.300; lower CI = 0.346, upper CI = 2.225). Experimental conditions had no effects on encoding preference (49.08 ± 2.15% vs. 47.69 ± 2.62%; t₍₁₈₎ = 0.389, p = 0.702). (C) A schematic of experimental design, together with the results showing the effects of dopamine D₁/D₅ receptor antagonist on contextual novelty-induced enhancement of memory retention in behavioral batch 4 is shown. Welch’s t-test revealed a significant decrease in 24-h memory for the SCH 23390-treated group (SCH, n = 16) compared with the vehicle-treated group (Veh, n = 17) (61.79 ± 2.95% vs. 53.67 ± 2.64%; t₍₃₁₎ = 2.046, p = 0.049). Effect size calculations revealed a moderately high Hedges’ g-value (g = − 0.695; lower CI = − 1.378, upper CI = − 0.002). Experimental conditions did not affect preference during encoding (50.50 ± 1.90% vs. 48.70 ± 2.14%; t₍₃₁₎ = 0.613, p = 0.546). All data are presented as mean ± SEM. *p < 0.05, **p < 0.01