Biomedical subjects

Florian Plattner

Publications and source records attributed to Florian Plattner.

9 recordsLinked to original sources

PubMed2006

Expression of p25 impairs contextual learning but not latent inhibition in mice.

The cyclin-dependent kinase 5 activator p25, which is derived from cleavage of p35, is thought to be formed in the brain of patients with Alzheimer's disease and schizophrenia. Female, but not male, transgenic mice expressing low levels of p25 have enhanced hippocampal long-term potentiation and improved spatial learning, raising the hypothesis that p25 may compensate for early learning deficits in Alzheimer's disease in a sex-dependent manner. Here, we show that low levels of p25 do not alter latent inhibition, a phenomenon that is impaired in patients with schizophrenia. We also demonstrate that contextual fear conditioning is impaired in female, but not in male, p25 transgenic mice. Thus, low levels of p25 are not always beneficial for learning as was previously hypothesized.

Analysis of Variance↗

PubMed2006

alphaCaMKII autophosphorylation: a fast track to memory.

Alpha Ca(2+)/calmodulin-dependent kinase II (alphaCaMKII), the major synaptic protein in the forebrain, can switch into a state of autonomous activity upon autophosphorylation. It has been proposed that alphaCaMKII autophosphorylation mediates long-term memory (LTM) storage. However, recent evidence shows that synaptic stimulation and behavioural training only transiently increase the autonomous alphaCaMKII activity, implicating alphaCaMKII autophosphorylation in LTM formation rather than storage. Consistent with this, mutant mice deficient in alphaCaMKII autophosphorylation can store LTM after a massed training protocol, but cannot form LTM after a single trial. Here, we review evidence that the role of alphaCaMKII autophosphorylation is in fact to enable LTM formation after a single training trial, possibly by regulating LTM consolidation-specific transcription.

Animals↗

PubMed2006

The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation.

Hyperphosphorylation of the microtubule-associated protein tau is a characteristic feature of neurodegenerative tauopathies including Alzheimer disease. Over-activation of proline-directed kinases, such as cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3 (GSK3), has been implicated in the aberrant phosphorylation of tau at proline-directed sites. In this study we tested the roles of Cdk5 and GSK3 in tau hyperphosphorylation in vivo using transgenic mice with p25-induced Cdk5 over-activation. We found that over-activation of Cdk5 in young transgenic animals does not induce tau hyperphosphorylation at sites recognized by the antibodies AT8, AT100, PHF-1, and TG3. In fact, we observed that Cdk5 over-activation leads to inhibition of GSK3. However, in old transgenic animals the inhibition of GSK3 is lost and results in increased GSK3 activity, which coincides with tau hyperphosphorylation at the AT8 and PHF-1 sites. Pharmacological inhibition of GSK3 in old transgenic mice by chronic treatment with lithium leads to a reduction of the age-dependent increase in tau hyperphosphorylation. Furthermore, we found that Cdk5, GSK3, and PP2A co-immunoprecipitate, suggesting a functional association of these molecules. Together, these results reveal the role of GSK3 as a key mediator of tau hyperphosphorylation, whereas Cdk5 acts as a modulator of tau hyperphosphorylation via the inhibitory regulation of GSK3. Furthermore, these findings suggest that disruption of regulation of GSK3 activity underlies tau hyperphosphorylation in neurodegenerative tauopathies. Hence, GSK3 may be a prime target for therapeutic intervention in tauopathies including Alzheimer disease.

Animals↗

PubMed2006

Autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse.

Autophosphorylation of alpha-Ca2+/calmodulin kinase II (alphaCaMKII) at Thr286 is thought to be a general effector mechanism for sustaining transcription-independent long-term potentiation (LTP) at pathways where LTP is NMDA receptor-dependent. We have compared LTP at two such hippocampal pathways in mutant mice with a disabling point mutation at the Thr286 autophosphorylation site. We find that autophosphorylation of alphaCaMKII is essential for induction of LTP at Schaffer commissural-CA1 synapses in vivo, but is not required for LTP that can be sustained over days at medial perforant path-granule cell synapses in awake mice. At these latter synapses LTP is supported by cyclic AMP-dependent signalling in the absence of alphaCaMKII signalling. Thus, the autophosphorylation of alphaCaMKII is not a general requirement for NMDA receptor-dependent LTP in the adult mouse.

Action Potentials↗

PubMed2006

Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory.

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with a multitude of functions. Although Cdk5 is widely expressed, it has been studied most extensively in neurons. Since its initial characterization, the fundamental contribution of Cdk5 to an impressive range of neuronal processes has become clear. These phenomena include neural development, dopaminergic function and neurodegeneration. Data from different fields have recently converged to provide evidence for the participation of Cdk5 in synaptic plasticity, learning and memory. In this review, we consider recent data implicating Cdk5 in molecular and cellular mechanisms underlying synaptic plasticity. We relate these findings to its emerging role in learning and memory. Particular attention is paid to the activation of Cdk5 by p25, which enhances hippocampal synaptic plasticity and memory, and suggests formation of p25 as a physiological process regulating synaptic plasticity and memory.

Animals↗

PubMed2005

Is there a role of the cyclin-dependent kinase 5 activator p25 in Alzheimer's disease?

Sporadic Alzheimer's disease is the leading cause of dementia, but the underlying molecular processes are still unknown. Several studies have observed an accumulation of the protein fragment p25 in sporadic Alzheimer's disease brain. p25 derives from proteolysis of p35, and overactivates the tau kinase cyclin-dependent kinase 5. Transgenic mice expressing high levels of p25 exhibit hyperphosphorylation of tau as seen in Alzheimer's disease, and neurodegeneration. In contrast, low-level p25 expression, less than half of endogenous p35 expression, has a sex-specific effect on hippocampal synaptic plasticity and improves spatial learning in female but not in male mice. Therefore, p25 formation may initially be a compensatory response for early learning deficits in Alzheimer's disease, but continued formation could contribute to detrimental changes in Alzheimer's disease.

Alzheimer Disease↗

PubMed2005

NCAM 180 acting via a conserved C-terminal domain and MLCK is essential for effective transmission with repetitive stimulation.

NCAM 180 isoform null neuromuscular junctions are unable to effectively mobilize and exocytose synaptic vesicles and thus exhibit periods of total transmission failure during high-frequency repetitive stimulation. We have identified a highly conserved C-terminal (KENESKA) domain on NCAM that is required to maintain effective transmission and demonstrate that it acts via a pathway involving MLCK and probably myosin light chain (MLC) and myosin II. By perfecting a method of introducing peptides into adult NMJs, we tested the hypothesized role of proteins in this pathway by competitive disruption of protein-protein interactions. The effects of KENESKA and other peptides on MLCK and MLC activation and on failures in both wild-type and NCAM 180 null junctions supported this pathway, and serine phosphorylation of KENESKA was critical. We propose that this pathway is required to replenish synaptic vesicles utilized during high levels of exocytosis by facilitating myosin-driven delivery of synaptic vesicles to active zones or their subsequent exocytosis.

4-Aminopyridine↗

PubMed2004

Distinct roles of different neural cell adhesion molecule (NCAM) isoforms in synaptic maturation revealed by analysis of NCAM 180 kDa isoform-deficient mice.

Mice that lack all three major isoforms of neural cell adhesion molecule (NCAM) (180 and 140 kDa transmembrane, and 120 kDa glycosylphosphatidylinositol linked) were previously shown to exhibit major alterations in the maturation of their neuromuscular junctions (NMJs). Specifically, even by postnatal day 30, they failed to downregulate from along their axons and terminals an immature, brefeldin A-sensitive, synaptic vesicle-cycling mechanism that used L-type Ca2+ channels. In addition, these NCAM null NMJs were unable to maintain effective transmitter output with high-frequency repetitive stimulation, exhibiting both severe initial depression and subsequent cyclical periods of total transmission failures that were of presynaptic origin. As reported here, mice that lack only the 180 kDa isoform of NCAM downregulated the immature vesicle-cycling mechanism on schedule, implicating either the 140 or 120 kDa NCAM isoforms in this important maturational event. However, 180 NCAM-deficient mice still exhibited many functional transmission defects. Although 180 NCAM null NMJs did not show the severe initial depression of NCAM null NMJs, they still had cyclical periods of complete transmission failure. In addition, several presynaptic molecules were expressed at lower levels or were more diffusely localized. Thus, the 180 kDa isoform of NCAM appears to play an important role in the molecular organization of the presynaptic terminal and in ensuring effective transmitter output with repetitive stimulation. Our results also suggest that PKC and MLCK (myosin light chain kinase) may be downstream effectors of NCAM in these processes. Together, these results indicate that different isoforms of NCAM mediate distinct and important events in presynaptic maturation.

Animals↗

PubMed2003

Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression.

Cleavage of the cyclin-dependent kinase 5 activator p35 generates the protein fragment p25, which accumulates in the forebrain of patients with Alzheimer's disease. Although p25 expression has been suggested to affect learning and memory, this hypothesis has not been tested to date. To investigate the role of p25 in hippocampus-dependent learning and memory we have generated transgenic mice expressing p25 preferentially in postnatal forebrain. p25 expression was highest in hippocampus where it averaged approximately 33% of endogenous p35 expression. This low level of p25 expression did not seem to result in hyperphosphorylation of tau, but increased the phosphorylation of neurofilament M and enhanced the expression of tau protein. These molecular changes did not correlate with neurodegeneration or motor abnormalities. In the Morris water maze the p25 mutants were normal in learning an initial platform location, but surprisingly reversal learning was improved when the platform position was changed. The p25 mutants were normal in contextual fear conditioning. However, when trained with a tone presentation the mutants showed reduced contextual conditioning and enhanced tone fear conditioning. We conclude that low p25 expression has pleiotropic effects on learning and memory. As p25 expression can improve learning and memory, p25 formation could be a compensatory mechanism for learning and memory deficits in Alzheimer's disease.

Alzheimer Disease↗