Centre for the Cellular Basis of Behaviour (CCBB)
Molecular Analysis of Memory
Professor Karl Peter Giese, PhD, Professor of Neurobiology of Mental Health
Area of research
Memory processes, including memory formation, storage, retrieval, and extinction, are fundamental for brain function and they are affected in various psychiatric illnesses such as mental retardation, Alzheimer’s disease, and post-traumatic stress disorder. Currently, the biological basis of memory processes is not sufficiently well understood to develop successful treatments for memory dysfunctions. However, the advent of sophisticated molecular techniques now allows for an advanced analysis of memory processes in experimental animals, which promises to be translated for the patients.
Lab description
Our team is studying mechanisms underlying hippocampus- and amygdala-dependent memory processes with the long-term aim to develop insights for treatments for memory dysfunctions in psychiatric illnesses. For our experiments were are using mice, which allows to combine state-of-the-art molecular experiments with behavioural studies.
Lost in space: After training in a swimming pool with a hidden platform normal wild-type (WT) mice and mutant mice lacking a particular kinase (CaMKKbeta) were asked to search for the platform. The selective search of WT mice indicated spatial memory, whereas the random search of the mutants revealed the lack of spatial memory. Interestingly, only male, but not female (not shown), mutants were impaired in spatial memory formation.
Memory-related gene regulation: Mouse 3 but not mouse 1 underwent contextual fear conditioning. The NGFI_B mRNA expression on coronal brain sections is shown. Contextual fear conditioning induced an up-regulation of NGFI-B in hippocampal area CA1 and controls showed that this up-regulation was specific for the learned context/shock association (not shown).
Main projects
1) The role of calcium/calmodulin-dependent protein kinases in memory processes.
We are studying the role of alphaCaMKII autophosphorylation and the function of CaMKK isoforms in hippocampus- and amygala-dependent memory processes. Our studies have disproved the hypothesis that alphaCaMKII autophosphorylation mediates memory storage and they have put forward the novel hypothesis that alphaCaMKII autophosphorylation is the molecular mechanism underlying (long-term) memory formation after a single episode/event. Consequently, it is conceivable that alphaCaMKII autophosphorylation is impaired in some forms of mental retardation. Furthermore, we have shown that the CaMKK isoforms have a male-specific role in memory formation. Thus, these isoforms might contribute to sexually dimorphic cognitive disorders.
2) Is formation of the Cdk5-activator p25 a compensation for learning deficits in Alzheimer’s disease?
Several investigators have detected the cleavage product p25 in post-mortem forebrain from patients with sporadic Alzheimer’s disease. We have generated transgenic mice expressing low levels of p25 and we have shown that low levels of p25 do not cause neurodegeneration but they improve spatial memory formation. Thus, we have proposed that p25 formation is a compensation for learning deficits in the early stages of Alzheimer’s disease. Now we are planning to study which molecular pathways are activated by p25 to improve memory formation.
3) Molecular analysis of reconsolidation of fear memory.
Memory retrieval can induce a process termed reconsolidation, which is essential for the maintenance of memory. Thus, blocking reconsolidation might be an opportunity to erase maladaptive and traumatic memories, which can cause post-traumatic stress disorder. With the long-term aim to erase traumatic memories we are studying molecular processes underlying reconsolidation of fear memory using functional genomic approaches.
Lab members
Keiko Mizuno, PhD
Kasia Radwanska, PhD
Cristian Bodo, PhD
Olivia Engmann, MSc (PhD student)
Laura Drinkwater, BSc (PhD student)
Selected publications
Giese KP (2007). Novel insights into the beneficial and detrimental actions of Cdk5. Mol. Interv. 7, 246-248.
Antunes-Martins A, Mizuno K, Irvine EE, Lepicard EM, Giese KP (2007). Sex-dependent up-regulation of two splicing factors, Psf and Srp20, during hippocampal memory formation. Learn. Mem. 14, 693-702.
Lamsa K, Irvine EE, Giese KP, Kullmann DM (2007). NMDA receptor-dependent long-term potentiation in mouse hippocampal interneurons shows a unique dependence on Ca2+/calmodulin-dependent kinases. J. Physiol. 584, 885-894.
Hojjati MR, van Woerden GM, Tyler WJ, Giese KP, Silva AJ, Pozzo-Miller LD, Elgersma Y (2007). Kinase activity is not required for αCaMKII-dependent presynaptic plasticity at hippocampal CA3-CA1 synapses. Nat. Neurosci. 10, 1125-1127.
Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, Gunn-Moore F, Verkhratsky A, Oddo S, La Ferla F, Giese KP, Dineley KT, Richardson JC, Yan SD, Hanger DP, Allan S, Sutherland C (2007). Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J. Neurochem. 103, 1132-1144.
Eickholt BJ, Ahmed AI, Davies M, Papakonstani EA, Pearce W, Starkey ML, Bilancio A, Need AC, Smith AJ, Hall SM, Hamers FP, Giese KP, Bradbury EL, Vanhaesebroeck B (2007). Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase. PLoS ONE 2, e869.
Cacucci F, Wills TJ, Lever C, Giese KP, O’Keefe J (2007). Experience-dependent increase in CA1 place cell spatial information, but not spatial reproducibility, is dependent on the autophosphorylation of alphaCaMKII. J. Neurosci. 27, 7854-7859.
Hooper C, Markevich V, Plattner F, Killick R, Schofield E, Engel T, Hernandez F, Anderton B, Rosenblum K, Bliss T, Cooke SF, Avila J, Lucas J, Giese KP, Stephenson J, Lovestone S (2007). Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur. J. Neurosci. 25, 81-86.
Parsley SL, Pilgram SM, Soto F, Giese KP, Edwards FA (2007). Enriching the environment of αCaMKIIT286A mutant mice reveals that LTD occurs in memory processing but must be subsequently reversed by LTP. Learn. Mem. 14, 84-93.
Mizuno K, Antunes-Martins A, Ris L, Peters M, Godaux E, Giese KP (2007). Ca2+/calmodulin kinase kinases β has a male-specific role in memory formation. Neuroscience 145, 393-402.
Mizuno K, Ris L, Sánchez-Capelo A, Godaux E, Giese KP (2006). Ca2+/calmodulin kinase kinases α is dispensable for brain development but is required for distinct memories in male, though not female, mice. Mol. Cell. Biol. 26, 9094-9104.
Mizuno K, Plattner F, Giese KP (2006). Expression of p25 impairs contextual learning but not latent inhibition in mice. Neuroreport 17, 1903-1905.
Irvine EE, von Hertzen LSJ, Plattner F, Giese KP (2006). alphaCaMKII autophosphorylation: a fast-track to memory. Trends Neurosci. 29, 459-465.
Plattner F, Angelo M, Giese KP (2006). The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau phosphorylation. J. Biol. Chem. 281, 25457-25465.
Angelo M, Plattner F, Giese KP (2006). Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory. J. Neurochem. 99, 353-370.
Cooke SF, Wu J, Plattner F, Errington M, Rowan M, Peters M, Hirano A, Anwyl R, Bliss TVP, Giese KP (2006). The autophosphorylation of a CaMKII is not a general requirement for NMDA receptor-dependent LTP. J. Physiol. (Lond.) 574, 805-818.
Pattinson D, Baccei M, Karadottir R, Torsney C, Moss A, McCutcheonJ, GieseKP, FitzgeraldM (2006). CaMKII a autophosphorylation is required for postnatal tuning of spinal sensory circuits. Mol. Cell. Neurosci. 33, 88-95.
ErskinePT, BeavenGDE, HaganR, WernerJ, WoodSP, VernonJ, GieseKP, Fox G, Cooper JB (2006). Structure of the neuronal protein calexcitin suggests a mode of interaction in signalling pathways of learning and memory. J. Mol. Biol. 357, 1536-1547.
Lepicard EM, Mizuno K, Martins-Antunes A, von Hertzen LSJ, Giese KP (2006). An endogenous inhibitor of calcium/calmodulin-dependent kinase II is up-regulated during consolidation of fear memory. Eur. J. Neurosci. 23, 3063-3070.
Irvine EE, Vernon J, Giese KP (2005). a CaMKII autophosphorylation contributes to rapid learning but is not necessary for memory. Nat. Neurosci. 8, 411-412.
von Hertzen LSJ, Giese KP (2005). Memory reconsolidation engages only a subset of immediate-early genes induced during consolidation. J. Neurosci. 25, 1935-1942.
Ris L, Angelo M, Plattner F, Capron B, Errington ML, Bliss TVP, Godaux E, Giese KP (2005). Sexual dimorphisms in the effect of low-level p25 expression on synaptic plasticity and memory. Eur. J. Neurosci. 21, 3023-3033.
von Hertzen LSJ, Giese KP (2005). a -isoform of Ca2+/calmodulin-dependent kinase II autophosphorylation is required for memory consolidation-specific transcription. NeuroReport 16, 1411-1414.
Giese KP, Ris L, Plattner F (2005). Is there a role of the Cdk5-activator p25 in Alzheimer’s disease? NeuroReport 16, 1725-1730.
Mizuno K, Giese KP (2005). Hippocampus-dependent memory formation: Do memory type-specific mechanisms exist? J. Pharmacol. Sci. 98, 191-197.
MurphyGG, Fedorov NB, Giese KP, Ohno M, Friedman E, Chen R, Silva AJ (2004). Increased neuronal excitability, synaptic plasticity and learning in aged K
Elgersma Y, Sweatt JD, Giese KP (2004). Mouse genetic approaches to investigating CaMKII function in plasticity and cognition. J. Neurosci. 24, 8410-8415.
Lengyel I, Voss K, Cammarota M, Bradshaw K, Brent V, Murphy KPSJ, Giese KP, Rostas JAP, Bliss TVP (2004). The autonomous activity of CaMKII is only transiently increased following the induction of long-term potentiation in the hippocampus. Eur. J. Neurosci. 20, 3063-3072.
Rogelj B, Giese KP (2004). Expression and function of brain-specific small RNAs. Rev. Neurosci. 15, 185-198.
Peters M, Mizuno K, Ris L, Angelo M, Godaux E, Giese KP (2003). Loss of Ca2+/calmodulin kinase kinase b affects the formation of some, but not all, types of hippocampus-dependent long-term memory. J. Neurosci. 23, 9752-9760.
Hardingham N, Glazewski S, PakhotinP, Mizuno K, Chapman PF, GieseKP, Fox K (2003). Neocortical LTP and experience-dependent synaptic plasticity require alphaCaMKII autophosphorylation. J. Neurosci. 23, 4428-4436.
Angelo M, Plattner F, Irvine EE, Giese KP (2003). Improved reversal learning and altered fear conditioning in transgenic mice with regionally restricted p25 expression. Eur. J. Neurosci. 18, 423-431.
Need AC, Irvine EE, Giese KP (2003). Learning impairments in K
RogeljB, Hartmann CEA, Yeo CH, Hunt SP, Giese KP (2003). Contextual fear conditioning regulates the expression of brain-specific small nucleolar RNAs in hippocampus . Eur. J. Neurosci. 18, 3089-3096.
Need AC, Giese KP (2003). Handling and environmental enrichment do not rescue learning and memory impairments in a CaMKIIT286A mutant mice. Genes Brain Behav. 2, 132-139.
Morcuende S, Gadd CA, Peters M, Moss A, Harris EA, Sheasby A, Fisher AS, de Felipe C, Mantyh PW, Rupniak NMJ, Giese KP, Hunt SP (2003). Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice. Eur.J. Neurosci. 18, 1828-1836.
Elgersma Y, Fedorov NB, Ikonen S, Choi ES, Elgersma M, Carvalho OM, Giese KP, Silva AJ (2002). Inhibitory autophosphorylation of CaMKII controls PSD association, plasticity and learning. Neuron 36, 493-505.
Giese KP, Peters M, Vernon J (2001). Modulation of excitability as learning and memory mechanism: A molecular genetic perspective. Physiol. Behav. 73, 803-810.
Giese KP, Friedman E, Telliez JB, Fedorov NB, Wines M, Feig LF, Silva AJ (2001). Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1). Neuropharmacology 41, 791-800.
Glazewski S, Giese KP, Silva A, Fox K (2000). The role of a -CaMKII autophosphorylation in neocortical experience-dependent plasticity. Nat. Neurosci. 3, 911-918.
Giese KP, Fedorov NB, Filipkowski RK Silva AJ (1998). Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science 279, 870-873.
Cho YH, Giese KP, Tanila H, Silva AJ, Eichenbaum H (1998). Abnormal hippocampal spatial representation in a CaMKIIT286A and CREB aD - mice. Science 279, 867-869.
Giese KP, Storm JF, Reuter D, Fedorov NB, Shao LR, Leicher T, Pongs O, Silva AJ (1998). Reduced K+ inactivation, spike broadening and after-hyperpolarization in K
Silva AJ, Smith A, Giese KP (1997). Gene targeting and the biology of learning and memory. Annu. Rev. Genet. 31, 527-546.
Silva AJ, Fedorov N, Kogan J, Frankland P, Coblentz J, Lundsten R, Friedman E, Smith A, Cho Y, Giese KP (1996). Genetic analysis of function and dysfunction in the central nervous system. Cold Spring Harb. Symp. Quant. Biol. 61, 239-246.