Perineuronal nets protect long-term memory by limiting activity-dependent inhibition from parvalbumin interneurons

Perineuronal nets (PNNs), a complex of extracellular matrix molecules that mostly surround GABAergic neurons in various brain regions, play a critical role in synaptic plasticity. The function and cellular mechanisms of PNNs in memory consolidation and reconsolidation processes are still not well understood. We hypothesized that PNNs protect long-term memory by limiting feedback inhibition from parvalbumin (PV) interneurons to projection neurons. Using behavioral, electrophysiological, and optogenetic approaches, we investigated the role of PNNs in fear memory consolidation and reconsolidation and GABAergic long-term potentiation (LTP). We made the discovery that the formation of PNNs was promoted by memory events in the hippocampus (HP), and we also demonstrated that PNN formation in both the HP and the anterior cingulate cortex (ACC) is essential for memory consolidation and reconsolidation of recent and remote memories. Removal of PNNs resulted in evident LTP impairments, which were rescued by acute application of picrotoxin, a GABAAreceptor blocker, indicating that enhanced inhibition was the cause of the LTP impairments induced by PNN removal. Moreover, removal of PNNs switched GABAAreceptor-mediated long-term depression to LTP through a presynaptic mechanism. Furthermore, the reduced activity of PV interneurons surrounded by PNNs regulated theta oscillations during fear memory consolidation. Finally, optogenetically suppressing PV interneurons rescued the memory impairment caused by removal of PNNs. Altogether, these results unveil the function of PV interneurons surrounding PNNs in protecting recent and remote contextual memory through the regulation of PV neuron GABA release.

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Memory Consolidation for Contextual and Auditory Fear Conditioning Is Dependent on Protein Synthesis, PKA, and MAP Kinase

Learning & Memory ◽

10.1101/lm.6.2.97 ◽

1999 ◽

Vol 6 (2) ◽

pp. 97-110 ◽

Cited By ~ 12

Author(s):

Glenn E. Schafe ◽

Nicole V. Nadel ◽

Gregory M. Sullivan ◽

Alexander Harris ◽

Joseph E. LeDoux

Keyword(s):

Protein Synthesis ◽

Map Kinase ◽

Fear Conditioning ◽

Memory Consolidation ◽

Molecular Mechanisms ◽

Short Term Memory ◽

Long Term Potentiation ◽

Fear Memory ◽

Term Memory

Fear conditioning has received extensive experimental attention. However, little is known about the molecular mechanisms that underlie fear memory consolidation. Previous studies have shown that long-term potentiation (LTP) exists in pathways known to be relevant to fear conditioning and that fear conditioning modifies neural processing in these pathways in a manner similar to LTP induction. The present experiments examined whether inhibition of protein synthesis, PKA, and MAP kinase activity, treatments that block LTP, also interfere with the consolidation of fear conditioning. Rats were injected intraventricularly with Anisomycin (100 or 300 μg), Rp-cAMPS (90 or 180 μg), or PD098059 (1 or 3 μg) prior to conditioning and assessed for retention of contextual and auditory fear memory both within an hour and 24 hr later. Results indicated that injection of these compounds selectively interfered with long-term memory for contextual and auditory fear, while leaving short-term memory intact. Additional control groups indicated that this effect was likely due to impaired memory consolidation rather than to nonspecific effects of the drugs on fear expression. Results suggest that fear conditioning and LTP may share common molecular mechanisms.

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Modeling memory consolidation during posttraining periods in cerebellovestibular learning

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1413798112 ◽

2015 ◽

Vol 112 (11) ◽

pp. 3541-3546 ◽

Cited By ~ 35

Author(s):

Tadashi Yamazaki ◽

Soichi Nagao ◽

William Lennon ◽

Shigeru Tanaka

Keyword(s):

Memory Consolidation ◽

Short Term Memory ◽

Mossy Fiber ◽

Long Term Potentiation ◽

Memory Formation ◽

Experimental Results ◽

Long Term Memory ◽

Optokinetic Response ◽

Term Memory

Long-term depression (LTD) at parallel fiber–Purkinje cell (PF–PC) synapses is thought to underlie memory formation in cerebellar motor learning. Recent experimental results, however, suggest that multiple plasticity mechanisms in the cerebellar cortex and cerebellar/vestibular nuclei participate in memory formation. To examine this possibility, we formulated a simple model of the cerebellum with a minimal number of components based on its known anatomy and physiology, implementing both LTD and long-term potentiation (LTP) at PF–PC synapses and mossy fiber–vestibular nuclear neuron (MF–VN) synapses. With this model, we conducted a simulation study of the gain adaptation of optokinetic response (OKR) eye movement. Our model reproduced several important aspects of previously reported experimental results in wild-type and cerebellum-related gene-manipulated mice. First, each 1-h training led to the formation of short-term memory of learned OKR gain at PF–PC synapses, which diminished throughout the day. Second, daily repetition of the training gradually formed long-term memory that was maintained for days at MF–VN synapses. We reproduced such memory formation under various learning conditions. Third, long-term memory formation occurred after training but not during training, indicating that the memory consolidation occurred during posttraining periods. Fourth, spaced training outperformed massed training in long-term memory formation. Finally, we reproduced OKR gain changes consistent with the changes in the vestibuloocular reflex (VOR) previously reported in some gene-manipulated mice.

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The role of PKMζ in the maintenance of long-term memory: a review

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0105 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Hamish Patel ◽

Reza Zamani

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Long Term Potentiation ◽

Global Memory ◽

Long Term Memory ◽

Compensatory Mechanism ◽

Term Memory ◽

Kinase C

Abstract Long-term memories are thought to be stored in neurones and synapses that undergo physical changes, such as long-term potentiation (LTP), and these changes can be maintained for long periods of time. A candidate enzyme for the maintenance of LTP is protein kinase M zeta (PKMζ), a constitutively active protein kinase C isoform that is elevated during LTP and long-term memory maintenance. This paper reviews the evidence and controversies surrounding the role of PKMζ in the maintenance of long-term memory. PKMζ maintains synaptic potentiation by preventing AMPA receptor endocytosis and promoting stabilisation of dendritic spine growth. Inhibition of PKMζ, with zeta-inhibitory peptide (ZIP), can reverse LTP and impair established long-term memories. However, a deficit of memory retrieval cannot be ruled out. Furthermore, ZIP, and in high enough doses the control peptide scrambled ZIP, was recently shown to be neurotoxic, which may explain some of the effects of ZIP on memory impairment. PKMζ knockout mice show normal learning and memory. However, this is likely due to compensation by protein-kinase C iota/lambda (PKCι/λ), which is normally responsible for induction of LTP. It is not clear how, or if, this compensatory mechanism is activated under normal conditions. Future research should utilise inducible PKMζ knockdown in adult rodents to investigate whether PKMζ maintains memory in specific parts of the brain, or if it represents a global memory maintenance molecule. These insights may inform future therapeutic targets for disorders of memory loss.

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Notch signalling becomes transiently attenuated during long-term memory consolidation in adult Wistar rats

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2007.04.006 ◽

2007 ◽

Vol 88 (3) ◽

pp. 342-351 ◽

Cited By ~ 26

Author(s):

Lisa Conboy ◽

Claire M. Seymour ◽

Marco P. Monopoli ◽

Niamh C. O’Sullivan ◽

Keith J. Murphy ◽

...

Keyword(s):

Memory Consolidation ◽

Wistar Rats ◽

Notch Signalling ◽

Long Term Memory ◽

Term Memory

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Noradrenergic Control of Long-Term Memory Consolidation

Catecholamine Research - Advances in Behavioral Biology ◽

10.1007/978-1-4757-3538-3_84 ◽

2002 ◽

pp. 353-356

Author(s):

Kazuto Kobayashi ◽

Yasunobu Yasoshima

Keyword(s):

Memory Consolidation ◽

Long Term Memory ◽

Term Memory

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Memory Consolidation and the Distinction between Short-Term and Long-Term Memory

The Future of the Brain Sciences ◽

10.1007/978-1-4899-6323-9_35 ◽

1969 ◽

pp. 335-340

Author(s):

Samuel Bogoch

Keyword(s):

Memory Consolidation ◽

Long Term Memory ◽

Short Term ◽

Term Memory

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The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics

Journal of Neurophysiology ◽

10.1152/jn.00370.2019 ◽

2019 ◽

Vol 122 (3) ◽

pp. 1123-1135 ◽

Cited By ~ 1

Author(s):

C. J. Scavuzzo ◽

M. J. LeBlancq ◽

F. Nargang ◽

H. Lemieux ◽

T. J. Hamilton ◽

...

Keyword(s):

Protein Synthesis ◽

Mitochondrial Function ◽

Neural Activity ◽

Memory Consolidation ◽

Hippocampal Neurons ◽

Membrane Properties ◽

Long Term Memory ◽

Term Memory ◽

Cellular Energetics

The nearly axiomatic idea that de novo protein synthesis is necessary for long-term memory consolidation is based heavily on behavioral studies using translational inhibitors such as anisomycin. Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors also have been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. In the present study, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30-min exposure to fast-bath-perfused anisomycin. Anisomycin suppressed protein synthesis to 46% of control levels as measured using incorporation of radiolabeled amino acids and autoradiography. During its application, anisomycin caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. Anisomycin-treated neurons also showed significant decreases in firing frequencies and spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. Because these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that anisomycin impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride and also impaired cytochrome c oxidase (complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that anisomycin-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical reevaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary. NEW & NOTEWORTHY Memory consolidation is thought to be dependent on the synthesis of new proteins because translational inhibitors produce amnesia when administered just after learning. However, these agents also disrupt basic neurobiological functions. We show that blocking protein synthesis disrupts basic membrane properties of hippocampal neurons that correspond to induced disruptions of mitochondrial function. It is likely that translational inhibitors cause amnesia through their disruption of neural activity as a result of dysfunction of intracellular energetics.

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