Showing papers by "Karl Peter Giese published in 2007"

Glycogen synthase kinase-3 inhibition is integral to long-term potentiation.

Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine ⁄threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3b is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3b phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3b. The LTP deficits can be attenuated ⁄rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3b in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer’s and other dementias.

Control of Axonal Growth and Regeneration of Sensory Neurons by the p110δ PI 3-Kinase

Abstract: The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110δ isoform has previously been shown to be enriched in leukocytes. Here we report that p110δ is also highly expressed in the nervous system. Inactivation of p110δ in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110δ activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110δ inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110δ, suggesting a key role of RhoA in p110δ signaling in neurons. Our data identify p110δ as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.

Experience-dependent increase in CA1 place cell spatial information, but not spatial reproducibility, is dependent on the autophosphorylation of the alpha-isoform of the calcium/calmodulin-dependent protein kinase II

Abstract: Place cells in hippocampal area CA1 are essential for spatial learning and memory. Here, we examine whether daily exposure to a previously unexplored environment can alter place cell properties. We demonstrate two previously unreported slowly developing plasticities in mouse place fields: both the spatial tuning and the trial-to-trial reproducibility of CA1 place fields improve over days. We asked whether these two components of improved spatial coding rely on the α-isoform of the calcium/calmodulin-dependent protein kinase II (αCaMKII) autophosphorylation, an effector mechanism of NMDA receptor-dependent long-term potentiation and an essential molecular process for spatial memory formation. We show that, in mice with deficient autophosphorylation of αCaMKII, the spatial tuning of place fields is initially similar to that of wild-type mice, but completely fails to show the experience-dependent increase over days. In contrast, place field reproducibility in the mutants, although impaired, does show the experience-dependent increase over days. Consequently, the progressive improvement in spatial coding in new hippocampal place cell maps depends on the existence of two molecularly dissociable, experience-dependent processes.

Kinase activity is not required for αCaMKII-dependent presynaptic plasticity at CA3-CA1 synapses

Abstract: Using targeted mouse mutants and pharmacologic inhibition of αCaMKII, we demonstrate that the αCaMKII protein, but not its activation, autophosphorylation or its ability to phosphorylate synapsin I, is required for normal short-term presynaptic plasticity Furthermore, αCaMKII regulates the number of docked vesicles independent of its ability to be activated These results indicate that αCaMKII has a nonenzymatic role in short-term presynaptic plasticity at hippocampal CA3-CA1 synapses

Novel insights into the beneficial and detrimental actions of cdk5.

Abstract: In the adult brain, cyclin-dependent kinase 5 (Cdk5) can be beneficial by contributing to memory formation or can be detrimental by causing neurodegeneration, and it is of great interest to understand this dichotomy. Currently, it remains largely unknown which mechanisms are regulated by Cdk5. Recent studies by Hawasli et al. and Qu et al., however, are significant advances towards mechanistic insights. Hawasli et al. demonstrate that Cdk5 regulates protease-directed degradation of an important synaptic receptor, which impacts memory formation. Qu et al. show that Cdk5 inhibits the activity of an enzyme that metabolizes reactive oxygen species, which then leads to neurodegeneration. These two studies hold promise for establishing treatments to prevent cognitive dysfunction and neurodegeneration.