Brain Physiology, Cognition and Consciousness: notice board entry
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Does Memory Storage Depend on Kinases?
- Posted by:
- Alfredo Pereira Jr (group admin)
- Date:
- 22 August 2007
- Comments:
- 5 comments
This paper (below) appeared in Science last week.
Does storage depend on the activation of only one kind of molecule?
Or is it dependent on the whole signal-transduction pathway (like a semeiotic process)?
Alfredo
Rapid Erasure of Long-Term Memory Associations in the Cortex by an Inhibitor of PKM
Reut Shema,1 Todd Charlton Sacktor,2 Yadin Dudai1*
Little is known about the neuronal mechanisms that subserve long-term memory persistence in the brain. The components of the remodeled synaptic machinery, and how they sustain the new synaptic or cellwide configuration over time, are yet to be elucidated. In the rat cortex, long-term associative memories vanished rapidly after local application of an inhibitor of the protein kinase C isoform, protein kinase M zeta (PKM). The effect was observed for at least several weeks after encoding and may be irreversible. In the neocortex, which is assumed to be the repository of multiple types of long-term memory, persistence of memory is thus dependent on ongoing activity of a protein kinase long after that memory is considered to have consolidated into a long-term stable form.
1 Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100, Israel.
2 Departments of Physiology, Pharmacology, and Neurology, The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Hi Alfredo,
Do you know if one gets this effect if the behavior in question has not been recently “called forth” so to speak? A colleague told me about some experiments in which the so-called “memory” was disruoted by certain protein-synthesis inhibitors only if they were given shortly after an experimental session in which the animals engaged in the relevent behavior. The session was NOT the first training session. The animals were well-trained in the task. So, the bottom line is that when an animal engages in some well trained behavior, the so-called “memory” is “reconsolidtated. In the experiments he was talking about, apparently, the protein-synthesis inhibitors did not “erase” the memory if the animals had not recently engaged in the relevant behavior. Know anything about this?
Glen
Hi Glen,
Your question is crucial for the interpretation of the reported results. I do not know the answer. Our group is receiving the adhesion of colleagues who are involved with this kind of experiment. We need your help, please!
Best,
Alfredo
Dear All:
I welcome our new members and invite to comment on our topics and notices.
Last year I participated of the Atlanta meeting of the Molecular and Cellular Cognition Society (this year I could not attend). My poster was about the possible role of CaMKII for consciousness and its inactivation during epileptic seizures. The main reference of my work was a paper by Yamagata et al. (1; see also 2).
Surprisingly, the person who was presenting a poster at the other side of the stand was Yamagata herself, with new work showing that genetically altered mice with reduced CaMKII expression had serious perceptual, cognitive and bahavioral deficits. I have been looking for the publication of her new work, but was not able to find it.
Best Regards to all,
Alfredo
(1) Neuroscience. 2006 Jul 7;140(3):981-92. Epub 2006 Apr 24.
A mechanism for the inactivation of Ca2+/calmodulin-dependent protein kinase II
during prolonged seizure activity and its consequence after the recovery from
seizure activity in rats in vivo.
Yamagata Y, Imoto K, Obata K.
Laboratory of Neurochemistry National Institute for Physiological Sciences,
Myodaiji, Okazaki 444-8787, Japan. yamagata@nips.ac.jp
Seizure is a form of excessive neuronal excitation and seizure-induced neuronal
damage has profound effects on the prognosis of epilepsy. In various seizure
models, the inactivation of Ca2+/calmodulin-dependent protein kinase II (CaMKII)
occurs during seizure activity preceding neuronal cell death. CaMKII is a
multifunctional protein kinase enriched in the brain and involved in various ways
the regulation of neuronal activity. CaMKII inactivation during seizure activity
may modify neuronal cell survival after seizure. However, the mechanism for
CaMKII inactivation and its consequence after seizure recovery remain to be
elucidated yet. In the present study, we employed a prolonged seizure model by
systemic injection of kainic acid into rats and biochemically examined the
activity state of CaMKII. In status epilepticus induced by kainic acid, not only
the inactivation of CaMKII in brain homogenate, but also a shift in the
distribution of CaMKII protein from the soluble to particulate fraction occurred
in both hippocampus and parietal cortex. The particulate CaMKII showed a large
decrease in the specific activity and a concurrent large increase in the
autophosphorylation ratio at Thr-286 (alpha) and at Thr-287 (beta). In contrast,
the soluble CaMKII showed normal or rather decreased specific activity and
autophosphorylation ratio. After 24 h of recovery from kainic acid-induced status
epilepticus, all such changes had disappeared. On the other hand, the total
amount of CaMKII was decreased by 35% in hippocampus and 20% in parietal cortex,
but the existing CaMKII was indistinguishable from those of controls in terms of
the autonomous activity ratio, specific activity and autophosphorylation ratio.
Thus, CaMKII inactivation in kainic acid-induced status epilepticus seems to be
derived not from simple degradation of the enzyme, but from the formation of the
autophosphorylated, inactivated and sedimentable CaMKII. Such a form of CaMKII
may be important during pathological conditions in vivo in preventing excessive
CaMKII activation due to Ca2+ overload.
Publication Types: Research Support, Non-U.S. Gov’t
PMID: 16632208 [PubMed – indexed for MEDLINE]
2: J Neurochem. 2004 Nov;91(3):745-54.
Ca2+/calmodulin-dependent protein kinase II is reversibly autophosphorylated,
inactivated and made sedimentable by acute neuronal excitation in rats in vivo.
Yamagata Y, Obata K.
Laboratory of Neurochemistry, National Institute for Physiological Sciences,
Myodaiji, Okazaki 444-8787, Japan. yamagata@nisp.ac.jp
Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is highly enriched in the
central nervous system, and is proposed to play important roles in
activity-dependent modifications of neuronal functions. We reported previously on
the dynamic regulation of the autonomous CaMKII in homogenates from hippocampus
and parietal cortex by acute neuronal excitation induced by electroconvulsive
treatment (ECT) in rats in vivo. In the present study, we examined in more detail
the biochemical changes in CaMKII under such conditions. We unexpectedly found a
concurrent increase in autophosphorylation at Thr286(alpha)/287(beta) and
decrease in the specific activity of CaMKII in the particulate fraction in either
hippocampus or parietal cortex during ECT-induced acute, brief seizure activity.
On the other hand, the soluble CaMKII showed a marked decrease in
autophosphorylation with unchanged or rather increased specific activity.
Increased autophosphorylation and decreased CaMKII activity were associated with
the detergent-insoluble particulate fraction. All these changes disappeared soon
after the termination of seizure activity. The reversible formation of such an
autophosphorylated, inactivated and sedimentable form of CaMKII during acute
neuronal excitation may indicate the existence of a novel regulatory mechanism of
CaMKII that may be important for normal functioning of the brain.
Publication Types: Research Support, Non-U.S. Gov’t
PMID: 15485503 [PubMed – indexed for MEDLINE]
One of the leading researchers about the role of kinases in learning and memory is Dr. J. David Sweatt, who is also the President of the Molecular and Cellular Cognition Society.
A lot of information about signaling pathways involving kinases can be found at his site
Best Regards,
Alfredo
Leptin, Kinases and Parkinson
From Science:
Food for Thought
John F. Foley
Parkinson’s disease is characterized by the loss of dopaminergic
neurons in
the substantia nigra pars compacta (SNc) of the brain. The reduced
production and function of neurotrophins (proteins that promote
neuronal
survival) in patients’ brains as compared to those of unaffected
individuals may be a contributing factor in Parkinson’s disease.
Leptin is
a hormone that functions in the hypothalamus to reduce appetite.
Leptin
receptors are also abundant in dopaminergic neurons in the SNc,
leading
Weng et al. to investigate whether leptin might play a role in
neuronal survival. Immunohistochemical analyses showed that
degeneration of
mouse dopaminergic neurons in the SNc caused by injection into the
brain of
the neurotoxin 6-OHDA (a mouse model of Parkinson’s disease) was less
severe if the mice were pre-injected with leptin. Leptin was also
protective against 6-OHDA-induced toxicity in mouse MN9D cells, a
dopaminergic cell line. Western blotting assays and treatments with
pharmacological inhibitors and short hairpin RNAs showed that the
ability
of leptin to block 6-OHDA-induced apoptosis was dependent on leptin
receptor-mediated activation of Janus kinase 2, mitogen-activated or
extracellular signal-regulated protein kinase kinase, extracellular
signal-regulated kinase 1 and 2, and the transcription factor
cAMP-response
element binding protein (CREB), a known neuronal survival factor.
Leptin
also stimulated the phosphorylation and nuclear localization of CREB
in
dopaminergic SNc neurons and increased the abundance of brain-derived
neurotrophic factor (BDNF) in the brain as compared to that in
untreated
animals. Together, these data suggest that treatment with leptin may
be
useful in therapies to combat Parkinson’s disease. —
JFF
J. Biol. Chem. 282, 34479 (2007).