Hippocampal Activation of Rac1 Regulates the Forgetting of Object Recognition Memory

Abstract

Forgetting is a universal feature for most types of memories. The best-defined and extensively characterized behaviors that depict forgetting are natural memory decay and interference-based forgetting [1, 2]. Molecular mechanisms underlying the active forgetting remain to be determined for memories in vertebrates. Recent progress has begun to unravel such mechanisms underlying the active forgetting [3-11] that is induced through the behavior-dependent activation of intracellular signaling pathways. In Drosophila, training-induced activation of the small G protein Rac1 mediates natural memory decay and interference-based forgetting of aversive conditioning memory [3]. In mice, the activation of photoactivable-Rac1 in recently potentiated spines in a motor learning task erases the motor memory [12]. These lines of evidence prompted us to investigate a role for Rac1 in time-based natural memory decay and interference-based forgetting in mice. The inhibition of Rac1 activity in hippocampal neurons through targeted expression of a dominant-negative Rac1 form extended object recognition memory from less than 72 hr to over 72 hr, whereas Rac1 activation accelerated memory decay within 24 hr. Interference-induced forgetting of this memory was correlated with Rac1 activation and was completely blocked by inhibition of Rac1 activity. Electrophysiological recordings of long-term potentiation provided independent evidence that further supported a role for Rac1 activation in forgetting. Thus, Rac1-dependent forgetting is evolutionarily conserved from invertebrates to vertebrates.

The Biology of Forgetting—A Perspective

“…Increased activation of Rac1 in the mouse hippocampus through targeted expression of constitutively active mutant Rac1 accelerates decay of object-recognition memory by about 3-fold (Liu et al, 2016). Conversely, inhibition of Rac1 activity by expressing a dominant-negative mutant Rac1 significantly prolongs memory.…”

Wilm’s tumor 1 promotes memory flexibility

“…Our results showing impaired subsequent learning after a first learning experience in the absence of WT1 suggest that the first learning is more strongly represented; hence, the mechanisms that counteract memory strengthening and consolidation normally are critical for 20 The authors declare no competing interests. Himmelreich…”

“…A key question is whether consolidated memories are weakened through a passive decay process, and/or by a learning-induced, active mechanisms that serves to promote memory flexibility. In other words, do signaling pathways that are activated during experience not only support consolidation, but also include counteracting molecular regulators that can decrease memory strength and favor forgetting 6 , such as the Rho family of GTPases signaling G proteins (Rac) [18][19][20] , scribble scaffolds 21 , DAMB dopamine receptors 22 , inhibition of AMPA receptor recycling 23,24 , and neurogenesis 5,25 ?…”

“…experiments, total RNA was extracted using Trizol (Thermo Fisher) from CA1 regions isolated from rat hippocampal slices (Control vs LTP 90 minutes). A pool of approximately 10 CA1 regions collected from at least 3 different animals were necessary in order20 to obtain approximately 1 µg of total RNA for each condition. For the experiment relative to Wt1∆ mice versus wild type littermates, dorsal hippocampi from naïve untrained animals were used.…”

The importance of forgetting: Limiting memory improves recovery of topological characteristics from neural data

“…For example, just as an increase in the number of AMPA receptors in the postsynaptic membrane is associated with increased memory, a decrease in this number via AMPA receptor endocytosis has recently been associated with forgetting [31]. Other work has shown that natural forgetting involves a protein called Rac [32, 33]—overexpression of Rac accelerates forgetting, and inhibition extends memory. On a longer timescale (thus less relevant to our work, but still interesting), another contributor to transience is hippocampal neurogenesis: the generation of neurons from stem cells in the dentate gyrus region of the hippocampal formation [34, 35].…”