Impaired Synaptic Plasticity and cAMP Response Element-Binding Protein Activation in Ca2+/Calmodulin-Dependent Protein Kinase Type IV/Gr-Deficient Mice

Department of Pediatrics, the Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2000; 20(17):6459-72.
Source: PubMed


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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Available from: Talal A Chatila, Aug 15, 2015
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    • "The data reveal that, even if we were concerned with only one induction protocol variable (i.e., the number of trains), we could find a wide variability in LTP durations. A single tetanus train usually destined to produce an early phase (Huang and Kandel, 1994; Abel et al., 1997; Winder et al., 1998; Zhuo et al., 2000; Barco et al., 2002; Woo and Nguyen, 2002; Chen et al., 2003; Ahmed and Frey, 2005a; Gelinas and Nguyen, 2005; Tsokas et al., 2005; Young and Nguyen, 2005; Costa-Mattioli et al., 2007; Ris et al., 2009) produces different durations extending from less than to approximately 1 h (Huang and Kandel, 1994, 1996; Qi et al., 1996; Abel et al., 1997; Winder et al., 1998; Ho et al., 2000; Zhuo et al., 2000; Matsushita et al., 2001; Miller et al., 2002; Woo and Nguyen, 2002; Alarcon et al., 2004; Barco et al., 2005; Huang et al., 2005; Meng et al., 2005; Tsokas et al., 2005; Young and Nguyen, 2005; Antion et al., 2008), approximately 2 h (Barad et al., 1998; Barco et al., 2002; Chen et al., 2003; Banko et al., 2005; Gelinas and Nguyen, 2005; Costa-Mattioli et al., 2007), 3 h (Reymann et al., 1985; Ahmed and Frey, 2005a; Ris et al., 2009), or 4 h (Cai et al., 2010). "
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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 · 3.33 Impact Factor
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    • "Knockout experiments have demonstrated the role of CaMKIV [76], ERK [15], CREB [77], [78] and TORC1 [60] in activity-dependent gene transcription. We analyzed the dependence of mRNA synthesis on these key molecules, for LTP and LTD inputs. "
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    ABSTRACT: Synaptic plasticity requires transcription and translation to establish long-term changes that form the basis for long term memory. Diverse stimuli, such as synaptic activity and growth factors, trigger synthesis of mRNA to regulate changes at the synapse. The palette of possible mRNAs is vast, and a key question is how the cell selects which mRNAs to synthesize. To address this molecular decision-making, we have developed a biochemically detailed model of synaptic-activity triggered mRNA synthesis. We find that there are distinct time-courses and amplitudes of different branches of the mRNA regulatory signaling pathways, which carry out pattern-selective combinatorial decoding of stimulus patterns into distinct mRNA subtypes. Distinct, simultaneously arriving input patterns that impinge on the transcriptional control network interact nonlinearly to generate novel mRNA combinations. Our model combines major regulatory pathways and their interactions connecting synaptic input to mRNA synthesis. We parameterized and validated the model by incorporating data from multiple published experiments. The model replicates outcomes of knockout experiments. We suggest that the pattern-selectivity mechanisms analyzed in this model may act in many cell types to confer the capability to decode temporal patterns into combinatorial mRNA expression.
    PLoS ONE 05/2014; 9(5):e95154. DOI:10.1371/journal.pone.0095154 · 3.23 Impact Factor
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    • "Insets are representative experiments. normal E-LTP and short-term memory (Ho et al., 2000). We have shown that thyroxin replacement therapy restores basal protein levels of CaMKIV previously reduced by hypothyroidism in area CA1 of the hippocampus of hypothyroid rats (Alzoubi et al., 2009). "
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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; 100. DOI:10.1016/j.brainresbull.2013.10.011 · 2.72 Impact Factor
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