A critical role for long-term potentiation mechanisms in the maintenance of object recognition memory in perirhinal cortex revealed by the infusion of zeta inhibitory pseudosubstrate

Abstract

Object recognition, the ability to discriminate between a novel and a familiar stimulus, is critically dependent upon the perirhinal cortex. Neural response reductions upon repetition of a stimulus, have been hypothesized to be the mechanism within perirhinal cortex that supports recognition memory function. Thus, investigations into the mechanisms of long-term depression (LTD) in perirhinal cortex has provided insight into the mechanism of object recognition memory formation, but the contribution of long-term potentiation (LTP) to object recognition memory formation has been less studied. Inhibition of atypical PKC activity by Zeta Inhibitory Pseudosubstrate (ZIP) impairs the maintenance of LTP but not LTD, thus here infusion of ZIP into the perirhinal cortex allowed us to investigate the contribution of LTP-like mechanisms to object recognition memory maintenance. Infusion of ZIP into the perirhinal cortex of rats 24 h after the sample phase impaired performance in an object recognition but not an object location task, in contrast infusion of ZIP into the hippocampus impaired performance in an object location but not an object recognition task. The impairment in object recognition by ZIP was prevented by administration of the peptide GluA23y, which blocks the endocytosis of GluA2 containing AMPA receptors. Finally, performance in a perceptual oddity task, which requires perirhinal cortex function, was not disrupted by ZIP. Together these results demonstrate the importance of LTP-like mechanisms to the maintenance of object recognition memory in the perirhinal cortex.

Infusing zeta inhibitory peptide into the perirhinal cortex of rats abolishes long-term object recognition memory without affecting novel object location recognition

“…We found that this intervention impairs the expression of recognition memory for novel objects, but not novel object locations, for both recent (1 day old) as well as remote (6 days old) memories. We thus replicate the findings of Outram et al (2022) , lending strong support to our respective results. Together with our earlier demonstration that infusing ZIP into the dorsal hippocampus disrupts long-term object location but not object identity memory, these data show that long-term memory for what has been encountered requires representations in perirhinal cortex, while memory for where things had been placed requires representations in dorsal hippocampus ( Winters, 2004 ; Forwood et al, 2005 ).…”

“…Taken together, these data suggest that processes underpinning LTD also promote object recognition memory in perirhinal cortex. Our data, as well as the findings from Outram et al (2022) , however, indicate that forms of synaptic plasticity involved in LTP also are critical for object recognition memory in this brain region. Specifically, the results of Outram et al (2022) show that the amnesic effects of ZIP on object recognition memory involve the internalization of GluA2/AMPARs, suggesting that maintaining long-lasting object recognition memory depends on forms of synaptic plasticity that are critical for LTP, but not LTD.…”

“…Our data, as well as the findings from Outram et al (2022) , however, indicate that forms of synaptic plasticity involved in LTP also are critical for object recognition memory in this brain region. Specifically, the results of Outram et al (2022) show that the amnesic effects of ZIP on object recognition memory involve the internalization of GluA2/AMPARs, suggesting that maintaining long-lasting object recognition memory depends on forms of synaptic plasticity that are critical for LTP, but not LTD. Thus, while these and our results seem in conflict with earlier findings, they make sense from the position that memory reflects patterns of synaptic connectivity arising from adjusting synaptic weights, i.e., the strengthening and weakening of synaptic connections, requiring processes involved in LTP as well as those involved in LTD ( Norman, 2010 ).…”

“…First, several studies have shown that despite ZIP-induced memory loss, animals are able to learn and form new long-term memories, suggesting that neurotoxic effects cannot readily account for the retrograde amnesia following infusions of ZIP ( Pastalkova et al, 2006 ; Sacktor, 2008 ; von Kraus et al, 2010 ). Second, the peptide GluA2-3Y that blocks the activity-dependent removal of GluA2/AMPARs ( Lee et al, 2002 ; Scholz et al, 2010 ; Migues et al, 2016 ) prevents the amnesic effects of ZIP, as we have shown before ( Migues et al, 2016 ) and ( Outram et al, 2022 ) have replicated. If indeed ZIP acts mainly via inducing excitotoxic effects, then preventing the removal of AMPA receptors from post-synaptic membranes should not block the actions of ZIP.…”

“…If indeed ZIP acts mainly via inducing excitotoxic effects, then preventing the removal of AMPA receptors from post-synaptic membranes should not block the actions of ZIP. Finally, non-specific actions of ZIP cannot account for why infusing it into the perirhinal cortex affects novel object recognition, but not the oddity discrimination task in the study of Outram et al (2022) . In conclusion, future studies could exploit this peptide to dissect the role and contributions of various brain areas during different phases of object recognition tasks more carefully ( Rossato et al, 2019 ).…”