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Agnes Thalhammer

Post Doc

Research Line

Neuroscience and Smart Materials

Center

IIT Central Research Labs Genova

Contacts

Largo Rosanna Benzi, 10, CBA Torre D1
Contact Me

About

Agnes Thalhammer studied Biochemistry at the University of Vienna, Austria, and subsequently received further training in protein chemistry at the Hormone Receptor Laboratory of Prof. JL Wittliff at the University of Louisville, Kentucky, USA. For her Ph.D., she joined the group of Prof. Michael Hollmann, first at the Max-Planck Institute for Experimental Medicine, Goettingen, and afterwards at the Ruhr-Universitaet Bochum, Germany, investigating the biophysical properties of glutamate receptors. She did her Postdoc in the group of Prof. Ralf Schoepfer at University College London (UCL), UK, where she investigated synaptic NMDAR-mediated calcium signaling and the postsynaptic density complex on a proteomic scale, in collaboration with Prof. Burlingame’s mass-spectrometry unit at UCSF. She joined the Italian Institute of Technology (IIT) as external consultant in 2013 and was awarded the Italian habilitation for biochemistry in 2014 and for physiology in 2018.

Projects

Synaptic adhesome 

My aim is to investigate synaptic cell adhesion at the proteomic scale. A comprehensive knowledge of the composition of the ‘synaptic adhesome’ is fundamental for understanding how the brain wires up and what goes wrong in neurodevelopmental diseases.

hipponeuron

 

There are about 1015 synapses in the human brain, which enable neurons to communicate with each other in a very specific and highly organized fashion. This shapes how we behave and think and, ultimately, who we are.

Synapses can be considered as asymmetric intercellular junctions specialized in mediating neuronal communication. Synaptic cell adhesion molecules (CAMs), which bridge the synaptic cleft between pre- and postsynaptic terminals, coordinate the function of the two sides of the synapse by mediating cell-cell recognition and signaling processes. Correct functioning of synaptic CAMs is required throughout the lifespan of a synapse, (i) for establishing the initial contact between pre- and postsynaptic neurons, (ii) for promoting and coordinating the assembly of the pre- and postsynaptic machinery, (iii) for conferring specific properties to a developing synapse and (iv) for remodeling synaptic structure and function in adulthood in an activity-dependent manner.

In each single synapse, these processes are mediated by dynamic and activity-dependent interactions involving multiple CAMs, rather than a single one. I refer to the full set of CAMs specifying a type of synapse as synaptic adhesome and postulate that the code for synaptic specificity must be searched at the level of the full synaptic adhesome. Likewise, the etiological mechanisms of connectopathies and synaptopathies can be understood only as perturbations affecting the composition of the full synaptic adhesome.

 

Current projects: 

 

itgautadhesome2c

 

  

Proteomic analysis of synaptic adhesomes – delineating signaling pathways altered in neurodevelopmental disorders

While the genetic origin of diseases such as autism and epilepsy is very heterogenous, a large proportion of gene mutations is affecting synaptic protein function and seem to converge on relatively few common pathways. The most intriguing question in the field of synaptopathies is how impairment of a single component can compromise correct function of synapses, molecular machineries consisting out of many hundreds of components. To address this, single aberrant protein function has to be studied in context of the affected interacting protein complexes and pathway components. Only when considering the full scale of alterations introduced by a single faulty synaptic protein, we can expect to identify possible targets for therapeutic strategies.

In this context, I am studying which signaling pathways are altered in synaptosomes of the integrin beta3 knock-out mouse, a well-established mouse model for autism spectrum disorder. Because integrins are as adhesion molecules easily accessible to pharmacological treatment, they present an ideal target for eventual therapeutic strategies for many ASD genes found affected in our integrin ASD mouse model.

 

  

 

 

 

 

 

 

Genome-editing approaches for personalized medicine in inherited diseases

This project aims to developing novel strategies for personalized medicine in inherited brain diseases with a complex and multifactorial genetic architecture. To this end, we employ CRISPR/Cas9-based genome-editing technology to correct the genetic defects at the base of inherited forms of autism and ataxia.

 

 

 

 

 

 

Sensor

 

Development of new sensors for simultaneous detection of Ca2+ and neurotransmitter release at single synapses

A long-standing goal in neuroscience has been to ‘see’ the Ca2+ that triggers synaptic transmission. The lab has engineered activity-dependent indicators to image Ca2+ signals and vesicle release in the same synapse in response to single action potentials, thus allowing simultaneous imaging of neurotramsmitter release and its trigger (Ca2+). The current spatial resolution for Ca2+ signal is at the level of single synapses (~1 µm). The lab aims to improve spatial resolution down to a single active zone (~200 nm), to directly detect the Ca2+ responsible for vesicle release. I am currently using these new approaches to investigate the contribution of voltage-gated calcium channel splice variants to synaptic plasticity and ataxia.

 

 

NDIntegrinsRed

 

 

 

 

 

 

 

  

 

 

Optimization of contacts between brain implant devices and neuronal cells by nano-structured diamond coatings and manipulation of integrin adhesion

An emerging therapeutic approach for a variety of neuropsychiatric disorders, such as Parkinson’s disease, epilepsy and depression, is to stimulate the patient’s neurons electrically with implants (the so called ‘brain pacemakers’). For this approach to succeed, the implant surface properties and the neuronal cell surface receptors are especially important since they must guarantee close apposition between the device and the neurons for optimal electrical stimulation. This project investigates the nature of the interface between nanodiamond-coated materials and neuronal/glial cell adhesion molecules with the ultimate goal of improving the long-term functionality of brain implants.

 

 

Master thesis and postgraduate internship training positions are available in our group at the Center for Synaptic Neuroscience and Technology (NSYN), IIT, Genoa.

For further information, please contact Dr. Agnes Thalhammer (agnes.thalhammer@iit.it) or Dr. Lorenzo Cingolani (lorenzo.cingolani@iit.it).

Jove

 

 

Selected Publications

Jaudon, F., Thalhammer, A. and Cingolani, L.A. (2019). Correction of beta3 integrin haplo-insufficiency by CRISPRa normalizes cortical network activity. BioRxiv/2019/664706. Full text

Thalhammer, A., Jaudon, F. and Cingolani, L.A. (2017) Combining Optogenetics with Artificial microRNAs to Characterize the Effects of Gene Knockdown on Presynaptic Function within Intact Neuronal Circuits. J. Vis. Exp. (133), e57223, doi:10.3791/57223.

Thalhammer, A., Contestabile, A., Ermolyuk, Y.S., Ng, T., Volynski, K.E., Soong, T.W., Goda, Y. and Cingolani, L.A. (2017) Alternative Splicing of P/Q-Type Ca2+ Channels Shapes Presynaptic Plasticity. Cell Reports, 20 (2), 333-343.full text

Ronzitti, G., Bucci, G., Emanuele, M., Leo, D., Sotnikova, T.D., Mus, L.V., Soubrane C.H., Dallas, M.L., Thalhammer, A., Cingolani, L.A., Mochida, S., Gainetdinov, R.R., Stephens, G. and Chieregatti, E. (2014) Exogenous alpha-synuclein decreases raft-partitioning of Cav2.2 channels inducing dopamine release. J. Neurosci, 34(32):10603–10615.

Thalhammer, A.*, Edgington, R.J.*, Welch, J., Bongrain, A., Bergonzo, P., Scorsone, E., Jackman, R.B. and Schoepfer, R. (2013) Patterned neuronal networks using nanodiamonds and the effect of varying nanodiamond properties on neuronal adhesion and outgrowth. J. Neural Engineering, 10, 056022. *Shared first-authorships.

Thalhammer, A. and Cingolani, L. (2013) Cell adhesion and homeostatic synaptic plasticity. Neuropharmacology, invited review for special issue on homeostatic plasticity, Neuropharmacology, 78, 23-30.

Thalhammer, A.*, Trinidad, J.C.*, Burlingame, A.L. and Schoepfer, R. Activity-dependent protein dynamics define interconnected cores of co-regulated postsynaptic proteins. (2013) Mol Cell Proteomics, 12, 29-41. *Shared first-authorships.

Trinidad, J.C., Barkan, D.T., Gulledge, B.F., Thalhammer, A., Sali, A., Schoepfer, R. and Burlingame, A.L. (2012) Global Identification and Characterization of Both O-GlcNAcylation and Phosphorylation at the Murine Synapse. Mol Cell Proteomics, 8, 215-229.

Thalhammer, A., Edgington, R.J., Cingolani, L.A., Schoepfer, R., and Jackman, R.B. (2010) The use of nanodiamond monolayer coatings to promote the formation of functional neuronal networks. Biomaterials, 31(8), 2097-2104.

Chalkley, R.J., Thalhammer, A., Schoepfer, R., and Burlingame, A.L. (2009). Identification of protein O-GlcNAcylation sites using electron transfer dissociation mass spectrometry on native peptides. Proc Natl Acad Sci U S A, 106(22), 8894-8899.

Thalhammer, A.*, Trinidad, J.C., Burlingame, A.L. and Schoepfer, R. (2009) Densin-180: revised membrane topology, domain structure and phosphorylation status. J Neurochem, 109(2), 297-302. *Co-corresponding author.

Cingolani, L.A., Thalhammer, A., Yu, L.M., Catalano, M., Ramos, T., Colicos, M.A., and Goda, Y. (2008) Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3 integrins. Neuron, 58(5), 749-762.

Trinidad, J.C., Thalhammer, A., Specht, C.G., Lynn, A.J., Baker, P.R., Schoepfer, R. and Burlingame, A.L. (2008) Quantitative Analysis of Synaptic Phosphorylation and Protein Expression. Mol Cell Proteomics7, 684-696.

Thalhammer, A., Rudhard, Y., Tigaret, C.M., Volynski, K.E., Rusakov, D.A. and Schoepfer, R. (2006) CaMKII translocation requires local NMDA receptor-mediated Ca2+ signaling. EMBO J25, 5873-5883.

Vosseller, K., Trinidad, J.C., Chalkley, R.J., Specht, C.G., Thalhammer, A., Lynn, A.J., Snedecor, J.O., Guan, S., Medzihradszky, K.F., Maltby, D.A., Schoepfer, R. and Burlingame, A.L. (2006) O-linked N-acetylglucosamine proteomics of postsynaptic density preparations using lectin weak affinity chromatography and mass spectrometry. Mol Cell Proteomics, 5, 923-934.

Tigaret, C.M., Thalhammer, A., Rast, G.F., Specht, C.G., Auberson, Y.P., Stewart, M.G. and Schoepfer, R. (2006) Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. Mol Pharmacol, 69, 1251-1259.

Trinidad, J.C., Specht, C.G., Thalhammer, A., Schoepfer, R. and Burlingame, A.L. (2006) Comprehensive identification of phosphorylation sites in postsynaptic density preparations. Mol Cell Proteomics, 5, 914-922.

Trinidad, J.C., Thalhammer, A., Specht, C.G., Schoepfer, R. and Burlingame, A.L. (2005) Phosphorylation state of postsynaptic density proteins. J Neurochem, 92, 1306-1316.

Specht, C.G., Tigaret, C.M., Rast, G.F., Thalhammer, A., Rudhard, Y. and Schoepfer, R. (2005) Subcellular localisation of recombinant alpha- and gamma-synuclein. Mol Cell Neurosci, 28, 326-334.

Thalhammer, A., Everts, I. and Hollmann, M. (2002) Inhibition by lectins of glutamate receptor desensitization is determined by the lectin's sugar specificity at kainate but not AMPA receptors. Mol Cell Neurosci, 21, 521-533.

Strutz, N., Villmann, C., Thalhammer, A., Kizelsztein, P., Eisenstein, M., Teichberg, V.I. and Hollmann, M. (2001) Identification of domains and amino acids involved in GLuR7 ion channel function. J Neurosci, 21, 401-411.

Thalhammer, A., Morth, T., Strutz, N. and Hollmann, M. (1999) A desensitization-inhibiting mutation in the glutamate binding site of rat alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits is dominant in heteromultimeric complexes. Neurosci Lett, 277, 161-164.

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I numeri di IIT

L’Istituto Italiano di Tecnologia (IIT) è una fondazione di diritto privato - cfr. determinazione Corte dei Conti 23/2015 “IIT è una fondazione da inquadrare fra gli organismi di diritto pubblico con la scelta di un modello di organizzazione di diritto privato per rispondere all’esigenza di assicurare procedure più snelle nella selezione non solo nell’ambito nazionale dei collaboratori, scienziati e ricercatori ”.

IIT è sotto la vigilanza del Ministero dell'Istruzione, dell'Università e della Ricerca e del Ministero dell'Economia e delle Finanze ed è stato istituito con la Legge 326/2003. La Fondazione ha l'obiettivo di promuovere l'eccellenza nella ricerca di base e in quella applicata e di favorire lo sviluppo del sistema economico nazionale. La costruzione dei laboratori iniziata nel 2006 si è conclusa nel 2009.

Lo staff complessivo di IIT conta circa 1440 persone. L’area scientifica è rappresentata da circa l’85% del personale. Il 45% dei ricercatori proviene dall’estero: di questi, il 29% è costituito da stranieri provenienti da oltre 50 Paesi e il 16% da italiani rientrati. Oggi il personale scientifico è composto da circa 60 principal investigators, circa 110 ricercatori e tecnologi di staff, circa 350 post doc, circa 500 studenti di dottorato e borsisti, circa 130 tecnici. Oltre 330 posti su 1400 creati su fondi esterni. Età media 34 anni. 41% donne / 59 % uomini.

Nel 2015 IIT ha ricevuto finanziamenti pubblici per circa 96 milioni di euro (80% del budget), conseguendo fondi esterni per 22 milioni di euro (20% budget) provenienti da 18 progetti europei17 finanziamenti da istituzioni nazionali e internazionali, circa 60 progetti industriali

La produzione di IIT ad oggi vanta circa 6990 pubblicazioni, oltre 130 finanziamenti Europei e 11 ERC, più di 350 domande di brevetto attive, oltre 12 start up costituite e altrettante in fase di lancio. Dal 2009 l’attività scientifica è stata ulteriormente rafforzata con la creazione di dieci centri di ricerca nel territorio nazionale (a Torino, Milano, Trento, Parma, Roma, Pisa, Napoli, Lecce, Ferrara) e internazionale (MIT ed Harvard negli USA) che, unitamente al Laboratorio Centrale di Genova, sviluppano i programmi di ricerca del piano scientifico 2015-2017.

IIT: the numbers

Istituto Italiano di Tecnologia (IIT) is a public research institute that adopts the organizational model of a private law foundation. IIT is overseen by Ministero dell'Istruzione, dell'Università e della Ricerca and Ministero dell'Economia e delle Finanze (the Italian Ministries of Education, Economy and Finance).  The Institute was set up according to Italian law 326/2003 with the objective of promoting excellence in basic and applied research andfostering Italy’s economic development. Construction of the Laboratories started in 2006 and finished in 2009.

IIT has an overall staff of about 1,440 people. The scientific staff covers about 85% of the total. Out of 45% of researchers coming from abroad 29% are foreigners coming from more than 50 countries and 16% are returned Italians. The scientific staff currently consists of approximately 60 Principal Investigators110 researchers and technologists350 post-docs and 500 PhD students and grant holders and 130 technicians. External funding has allowed the creation of more than 330 positions . The average age is 34 and the gender balance proportion  is 41% female against 59% male.

In 2015 IIT received 96 million euros in public funding (accounting for 80% of its budget) and obtained 22 million euros in external funding (accounting for 20% of its budget). External funding comes from 18 European Projects, other 17 national and international competitive projects and approximately 60 industrial projects.

So far IIT accounts for: about 6990 publications, more than 130 European grants and 11 ERC grants, more than 350 patents or patent applications12 up start-ups and as many  which are about to be launched. The Institute’s scientific activity has been further strengthened since 2009 with the establishment of 11 research nodes throughout Italy (Torino, Milano, Trento, Parma, Roma, Pisa, Napoli, Lecce, Ferrara) and abroad (MIT and Harvard University, USA), which, along with the Genoa-based Central Lab, implement the research programs included in the 2015-2017 Strategic Plan.