Forgetting of long-term memory requires activation of NMDA receptors, L-type voltage-dependent Ca2+ channels, and calcineurin

Abstract

In the past decades, the cellular and molecular mechanisms underlying memory consolidation, reconsolidation, and extinction have been well characterized. However, the neurobiological underpinnings of forgetting processes remain to be elucidated. Here we used behavioral, pharmacological and electrophysiological approaches to explore mechanisms controlling forgetting. We found that post-acquisition chronic inhibition of the N-methyl-D-aspartate receptor (NMDAR), L-type voltage-dependent Ca2+ channel (LVDCC), and protein phosphatase calcineurin (CaN), maintains long-term object location memory that otherwise would have been forgotten. We further show that NMDAR activation is necessary to induce forgetting of object recognition memory. Studying the role of NMDAR activation in the decay of the early phase of long-term potentiation (E-LTP) in the hippocampus, we found that ifenprodil infused 30 min after LTP induction in vivo blocks the decay of CA1-evoked postsynaptic plasticity, suggesting that GluN2B-containing NMDARs activation are critical to promote LTP decay. Taken together, these findings indicate that a well-regulated forgetting process, initiated by Ca2+ influx through LVDCCs and GluN2B-NMDARs followed by CaN activation, controls the maintenance of hippocampal LTP and long-term memories over time.

Ifenprodil infusion in agranular insular cortex alters social behavior and vocalizations in rats exposed to moderate levels of ethanol during prenatal development

“…The dose of ifenprodil used in this study (1 μg in 0.3 μl per hemisphere) is comparable to doses of ifenprodil used by other groups to investigate how antagonizing GluN2B-containing NMDA receptors affects neuronal physiology and behaviors mediated by certain brain regions [60, 99, 100]. This dose of ifenprodil has the potential to cause off-target effects, however.…”

Retroactive Interference: Forgetting as an Interruption of Memory Consolidation

“…Given that consolidation decreases the fragility of memory traces, theories and studies related to memory should address consolidation as an infl uential phenomenon in this process (Brown, 2002). From a neurophysiological perspective, forgetting eventually mobilizes physiological mechanisms that mediate time-dependent forgetting (Dong et al, 2016;Sachser et al, 2016;Villareal, Do, Haddad, & Derrick, 2002). According to these recent fi ndings, memory can last indefi nitely, provided it is protected from the active forgetting associated with specifi c neurochemical mechanisms.…”

Pb(II) Disruption of Synaptic Activity Through Ca(II)- and Zn(II)-binding Proteins

“…Calcineurin (CaN) is a serine/threonine protein phosphatase associated with activation of T cells, and which appears to also play an important role in cognitive function and long-term memory [108,133] . The function of heterodimeric CaN is regulated by binding of the Ca 2+ /CaM complex in the CaM binding domain (Figure 2) [133] , and thus, there are multiple points within this signaling pathway where Pb 2+ can disrupt normal activities through replacement of Ca 2+ or Zn 2+ or a mechanism of opportunistic binding.…”

“…The function of heterodimeric CaN is regulated by binding of the Ca 2+ /CaM complex in the CaM binding domain (Figure 2) [133] , and thus, there are multiple points within this signaling pathway where Pb 2+ can disrupt normal activities through replacement of Ca 2+ or Zn 2+ or a mechanism of opportunistic binding.…”