Impaired Synaptic Plasticity and cAMP Response Element-Binding Protein Activation in Ca2+/Calmodulin-Dependent Protein Kinase Type IV/Gr-Deficient Mice
ABSTRACT The Ca(2+)/calmodulin-dependent protein kinase type IV/Gr (CaMKIV/Gr) is a key effector of neuronal Ca(2+) signaling; its function was analyzed by targeted gene disruption in mice. CaMKIV/Gr-deficient mice exhibited impaired neuronal cAMP-responsive element binding protein (CREB) phosphorylation and Ca(2+)/CREB-dependent gene expression. They were also deficient in two forms of synaptic plasticity: long-term potentiation (LTP) in hippocampal CA1 neurons and a late phase of long-term depression in cerebellar Purkinje neurons. However, despite impaired LTP and CREB activation, CaMKIV/Gr-deficient mice exhibited no obvious deficits in spatial learning and memory. These results support an important role for CaMKIV/Gr in Ca(2+)-regulated neuronal gene transcription and synaptic plasticity and suggest that the contribution of other signaling pathways may spare spatial memory of CaMKIV/Gr-deficient mice.
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ABSTRACT: Long-term potentiation (LTP) remains the most widely accepted model for learning and memory. In accordance with this belief, the temporal differentiation of LTP into early and late phases is accepted as reflecting the differentiation of short-term and long-term memory. Moreover, during the past 30 years, protein synthesis inhibitors have been used to separate the early, protein synthesis-independent (E-LTP) phase and the late, protein synthesis-dependent (L-LTP) phase. However, the role of these proteins has not been formally identified. Additionally, several reports failed to show an effect of protein synthesis inhibitors on LTP. In this review, a detailed analysis of extensive behavioral and electrophysiological data reveals that the presumed correspondence of LTP temporal phases to memory phases is neither experimentally nor theoretically consistent. Moreover, an overview of the time courses of E-LTP in hippocampal slices reveals a wide variability ranging from <1 h to more than 5 h. The existence of all these conflictual findings should lead to a new vision of LTP. We believe that the E-LTP vs. L-LTP distinction, established with protein synthesis inhibitor studies, reflects a false dichotomy. We suggest that the duration of LTP and its dependency on protein synthesis are related to the availability of a set of proteins at synapses and not to the de novo synthesis of plasticity-related proteins. This availability is determined by protein turnover kinetics, which is regulated by previous and ongoing electrical activities and by energy store availability.Reviews in the neurosciences 05/2015; DOI:10.1515/revneuro-2014-0072 · 3.31 Impact Factor
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ABSTRACT: Cyclic-AMP response element binding protein (CREB) is a transcription factor crucial for late phase long-term potentiation (L-LTP) induction and maintenance. Upon Multiple high frequency stimulation (MHFS), large Ca(2+) influx activates adenylyl cyclase. This, in turn, activates PKA, which by itself or through MAPK p42/p44 can activate (phosphorylate) CREB. Upon phosphorylation, P-CREB activates multiple genes essential for L-LTP generation. Calcium calmodulin kinase IV (CaMKIV) is also activated by calcium and can directly activate CREB. We have shown previously that hypothyroidism impairs L-LTP and reduces the basal protein levels of CREB, MAPK p42/p44, and CaMKIV in area CA1 of the hippocampus. In the present study, levels of these signaling molecules were determined in area CA1 during the induction and maintenance phases of L-LTP. Standard MHFS was used to evoke L-LTP in the CA1 area of hypothyroid, levothyroxin treated hypothyroid and sham control anaesthetized adult rats. Chronic levothyroxin treatment reversed hypothyroidism-induced L-LTP impairment. Five minutes after MHFS, western blotting showed an increase in the levels of P-CREB, and P-MAPK p42/p44 in sham-operated control, and levothyroxin treated hypothyroid animals, but not in hypothyroid animals. The protein levels of total CREB, total MAPK p42/p44, BDNF and CaMKIV were not altered in all groups five minutes after MHFS. Four hours after MHFS, the levels of P-CREB, and P-MAPK p42/p44 remained unchanged in hypothyroid animals, while they were elevated in sham-operated control, and levothyroxin treated hypothyroid animals. We conclude that normalized phosphorylation of essential kinases such as P-CREB and P-MAPK p42/p44 may account for restoration of normal L-LTP induction and maintenance in the CA1 area of levothyroxin-treated hypothyroid animals.Brain research bulletin 11/2013; DOI:10.1016/j.brainresbull.2013.10.011 · 2.97 Impact Factor
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ABSTRACT: Weakly tetanized synapses in area CA1 of the hippocampus that ordinarily display long-term potentiation lasting approximately 3 h (called early-LTP) will maintain a longer-lasting change in efficacy (late-LTP) if the weak tetanization occurs shortly before or after strong tetanization of an independent, but convergent, set of synapses in CA1. The synaptic tagging and capture hypothesis explains this heterosynaptic influence on persistence in terms of a distinction between local mechanisms of synaptic tagging and cell-wide mechanisms responsible for the synthesis, distribution, and capture of plasticity-related proteins (PRPs). We now present evidence that distinct CaM kinase (CaMK) pathways serve a dissociable role in these mechanisms. Using a hippocampal brain-slice preparation that permits stable long-term recordings in vitro for >10 h and using hippocampal cultures to validate the differential drug effects on distinct CaMK pathways, we show that tag setting is blocked by the CaMK inhibitor KN-93 (2-[N-(2-hydroxyethyl)]-N-(4-methoxybenzenesulfonyl)amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) that, at low concentration, is more selective for CaMKII. In contrast, the CaMK kinase inhibitor STO-609 [7H-benzimidazo(2,1-a)benz(de)isoquinoline-7-one-3-carboxylic acid] specifically limits the synthesis and/or availability of PRPs. Analytically powerful three-pathway protocols using sequential strong and weak tetanization in varying orders and test stimulation over long periods of time after LTP induction enable a pharmacological dissociation of these distinct roles of the CaMK pathways in late-LTP and so provide a novel framework for the molecular mechanisms by which synaptic potentiation, and possibly memories, become stabilized.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2010; 30(14):4981-9. DOI:10.1523/JNEUROSCI.3140-09.2010 · 6.75 Impact Factor