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Cells & behaviour

Memory mechanisms in health & disease

The research group is led by Karl Peter Giese, PhD, Professor of Neurobiology of Mental Health.

Professor Giese is also a rember if the KCL Alzheimer's Research UK committee.

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 Alzheimer’s disease, autism, post-traumatic stress disorder and schizophrenia. 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.

Main Projects

1) The role of p25-regulated proteins in Alzheimer's disease.

Recently, we have demonstrated for the first time that p25, a truncated form of the protein p35, is generated in the hippocampus during spatial memory formation (Engmann et al., 2011, Biol Psychiatry). Further, we have shown that p25 expression is reduced in the early stages of Alzheimer’s disease. Therefore, we have proposed that p25 generation is a memory mechanism that is impaired in Alzheimer’s disease. Further, we have found that p25 generation induces the expression of proteins that regulate synaptogenesis. Currently, we are studying whether dysfunctions of p25-regulated proteins cause cognitive deficits and neurodegeneration in Alzheimer’s disease.

Reduced p25 expression in post-mortem hippocampus of AD patients        p25 is generated in hippocampus of mice during spatial memory formation

2) Discovery of a novel memory mechanism

Recently, we have shown for the first time that generation of multi-innervated spines, a specific type of synapse, contributes to long-term memory formation when synaptic strengthening is impaired (Radwanska et al., 2011). Currently, we are studying whether generation of multi-innervated spines contributes to cognitive deficits in various disease models.

An example of a multi-innervated spine

3) Regulation of CaMKII

CaMKII is major synaptic kinase that plays a key role in memory formation. Dysregulations in CaMKII signalling have been linked with Alzheimer’s disease and schizophrenia. Currently, we are exploring approaches to study the role of CaMKII in memory storage and we attempt to rescue CaMKII dysfunction in mouse models of disease (see, Lucchesi et al., 2011).

A model for CaMKII endogenous inhibitors as plasticity-related proteins

4) Epigenetics of memory storage

Recently, we have discovered long-lasting changes in gene expression after training in memory tasks. Currently, we are studying how long lasting these changes are and whether they are linked to lasting epigenetic modifications.

5) Sex differences in memory formation

As illustrated in the figure (Mizuno and Giese, 2010), there are substantial sex differences in molecular mechanisms underlying synaptic plasticity, many of which we have identified. Currently, we investigating these fundamental differences.

Image 5

Summary of recently identified sexdifference in molecular signalling underlying memory formation

Current Lab Members

  • Keiko Mizuno, PhD
  • Wajeeha Aziz, PhD
  • Fabio Vigil, MSc (PhD student)
  • Anshua Ghosh, MSc (PhD student)

Previous Lab Members

  • Marco Angelo, PhD awarded
  • Ana Antunes-Martins, PhD awarded
  • Cristian Bodo, PhD
  • Laura Drinkwater, PhD awarded
  • Olivia Engmann, PhD awarded
  • Elaine E. Irvine, PhD
  • Eve Lepicard, PhD
  • Walter Lucchesi, PhD
  • Anna C. Need, PhD awarded
  • Grace S. Pereira, PhD
  • Marco Peters, PhD awarded
  • Florian Plattner, PhD awarded
  • Kasia Radwanska, PhD
  • Laurence Ris, PhD
  • Boris Rogelj, PhD
  • Amelia Sanchez-Capelo, PhD
  • Sachin Tiwari, PhD to be awarded
  • Jeffrey Trickett, PhD
  • Jeffrey Vernon, PhD
  • Laura S.J. von Hertzen, PhD awarded

Selected Publications

GIESE KP (2014). Generation of the Cdk5 activator p25 is a memory mechanism that is affected in early Alzheimer’s disease. Front. Mol. Neurosci. 7, 36.

GIESE KP, Mizuno K (2013). The roles of protein kinases in learning and memory. Learn. Mem. 20, 540-552.

Easton AC, Lucchesi W, Lourdusamy A, Lenz B, Solati J, Golub Y, Lewczuck P, Fernandes C., Desrivieres S, Dawris RR, Moll GH, Kornhuber J, Frank J, Hoffmann P, Soyka M, Kiefer F, GESGA consortium, Schumann G, GIESE KP, Mueller CP (2013). aCaMKII autophosphorylation controls the establishment of alcohol drinking behaviour. Neuropsychopharmacology 38, 1636-1647.

Mizuno K, Dempster E, Mill J, GIESE KP (2012). Long-lasting regulation of hippocampal Bdnf gene transcription after contextual fear conditioning. Genes Brain Behav. 11, 651-659.

Radwanska K, Medvedev N, Pereira GS, Engmann O, Thiede N, Moraes MFD, Villers A, Irvine EE, Maunganidze N, Pyza E, Ris L, Szymanska M, Lipinski M, Kaczmarek L, Stewart MG, GIESE KP (2011). Mechanism of long-term memory formation when synaptic strengthening is impaired. Proc. Natl. Acad. Sci. USA, 108, 18741-18745.

Engmann O, Hortobagyi T, Pidsley R, Troakes C, Bernstein HG, Kreutz MR, Mill J, Nikolic M, GIESE KP (2011). Schizophrenia is associated with dysregulation of a Cdk5 activator p35 that regulates synaptic protein expression and cognition. Brain 134, 2408-2421.

Engmann O, Hortobagyi T, Thompson AJ, Guadagno J, Troakes C, Soriano S, Al-Sarraj S, Kim Y, GIESE KP (2011). Cdk5 activator p25 is generated during memory formation and is reduced at an early stage in Alzheimer’s disease. Biol. Psychiatry 70, 159-168.

Irvine EE, Drinkwater L, Radwanska K, Al-Qassab H, Smith MA, O’Brien M, Kielar C, Choudhary AI, Krauss S, Cooper J, Wither DJ, GIESE KP (2011). Insulin receptor substrate 2 is a negative regulator of memory formation. Learn. Mem. 18, 375-383.

Mizuno K, GIESE KP (2010). Towards a molecular understanding of sex differences in memory formation. Trends Neurosci. 33, 285-291.

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.

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.

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.

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.

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.

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.

Murphy GG, Fedorov NB, GIESE KP, Ohno M, Friedman E, Chen R, Silva AJ (2004). Increased neuronal excitability, synaptic plasticity and learning in aged Kv b 1.1 knockout mice. Curr. Biol. 14, 1907-1915.

Elgersma Y, Sweatt JD, GIESE KP (2004). Mouse genetic approaches to investigating CaMKII function in plasticity and cognition. J. Neurosci. 24, 8410-8415.

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, GIESE KP, Fox K (2003). Neocortical LTP and experience-dependent synaptic plasticity require alphaCaMKII autophosphorylation. J. Neurosci. 23, 4428-4436.

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.

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.

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 Kvß1.1-deficient mice with impaired learning. Learn. Mem. 5, 257-273.

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.

Silva AJ, Smith A, GIESE KP (1997). Gene targeting and the biology of learning and memory. Annu. Rev. Genet. 31, 527-546.

Martini R, Mohajeri MH, Kasper S, GIESE KP, Schachner M (1995). Mice doubly deficient in the genes for P0 and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J. Neurosci. 15, 4488-4495.

Martini R, Zielasek J, Toyka KV, GIESE KP, Schachner M (1995). Protein zero (P0)-deficient mice show myelin degeneration in peripheral nerves characteristic of inherited human neuropathies. Nat. Genet. 11, 281-286.

Silva AJ, GIESE KP (1994). Plastic genes are in! Curr. Opin. Neurobiol. 4, 413-420.

Montag D, GIESE KP, Bartsch U, Martini R, Lang Y, Blüthmann H, Karthigasan J, Kirschner DA, Wintergerst ES, Nave KA, Lipp HP, Schachner M (1994). Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13, 229-246.

GIESE KP, Martini R, Lemke G, Soriano P, Schachner M (1992). Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell 71, 565-576.

Stühmer W, Ruppersberg JP, Schröter KH, Sakmann B, Stocker M, GIESE KP, Perschke A, Baumann A, Pongs O (1989). Molecular basis of the functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J. 8, 3235-3244.

 

 

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