CNUP Training Faculty

Oliver Schluter, M.D., Ph.D.

Assistant Professor, Neuroscience

M.D., University of Gottingen ()
Ph.D. University of Hannover (2000)

Office: 445 Crawford Hall
Telephone:412-624-1876
Fax:412-624-9198
E-mail: schluter@pitt.edu
Website:

Cellular and molecular mechanisms of physiological and pathophysiological synaptic plasticity

Research Summary:

Experience changes the pattern and strength of connections between neurons in our brains. These processes, subsumed under the terms structural and synaptic plasticity, are the cellular correlates of learning and memory. NMDA-type glutamate receptor-dependent forms of synaptic plasticity, including long-term synaptic depression (LTD) and potentiation (LTP) at principal neurons, are the predominant forms for these long-term changes, which often change the connectivity persistently. While NMDA receptor activation is required for the induction of synaptic plasticity, changes in synaptic strength are expressed as changes in the number of AMPA-type glutamate receptors in the synapse. More than 100 proteins have been discovered to be involved in these processes. However, the signaling cascade, which links NMDA receptor signaling to changes in AMPA receptor numbers remains unknown. Our research goal is to understand the molecular underpinnings of signaling during synaptic plasticity, both during physiological learning (e.g. developmental plasticity) and pathological learning, as e.g. upon exposure to drugs of abuse. We use genetic approaches, including molecular replacements to manipulate individual proteins and even single amino acids of them, in rodents in combination with biochemical and electrophysiological methods to identify the molecular and cellular consequences. Combining it with behavioral assays, we aim to gain an understanding from the molecular over the cellular to the system level.

We hypothesize that signaling scaffolds of the disc-large (DLG)-membrane associated guanylate kinases (MAGUKs) coordinate these signaling processes. The four protein family members, PSD-93, PSD-95, SAP97 and SAP102, functionally interact to potentially ensure signaling specificity by linking NMDA receptors to specific signaling machineries and effector proteins, such as AMPA receptors. As an immediate goal, we aim to link each of the DLG-MAGUKs to specific signaling processes in synaptic plasticity. PSD-95 e.g. links calcineurin via AKAP150 to LTD induction. Furthermore, PSD-95 is required for experience-dependent maturation and stabilization of nascent synapses, showing that one family member is involved in different signaling processes. Linking these functions to specific domains of a single DLG-MAGUK will eventually allow us to study the specific function of this signaling process in vivo by generating respective mutant mouse lines.

Selected Publications:

Huang, X.*, Stodieck, S.K.*, Goetze, B., Cui, L., Wong, M.H., Wenzel, C,, Hosang, L., Dong, Y., Löwel, S#., Schlüter, O.M#. Progressive Maturation of Silent Synapses Governs the Duration of a Critical Period. PNAS. 112(24): E3131-40, 2015.

Ma, Y-Y., Lee, B.R., Wang, X., Guo, C., Liu, L., Cui, R., Lan, R., Lan, Y., Balcita-Pedicino, J.J., Wolf, M.E., Sesack, S.R., Shaham, Y., Schlüter, O.M., Huang, Y.H., Dong, Y. Bidirectional Modulation of Incubation of Cocaine Craving by Silent Synapse-Based Remodeling of Prefrontal Cortex to Accumbens Projections. Neuron 83(6): 1453-67, 2014.

Greifzu, F., Pielecka-Fortuna, J., Kalogeraki, E., Krempler, K., Favaro, P.D., Schlüter, O.M., Löwel, S. Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity. PNAS 111(3):1150-5, 2014.

Lee, B.R.*, Ma, Y.*, Huang, Y.H., Wang, X., Otaka, M., Ishikawa, M., Neumann, P.A., Graziane, N.M., Brown, T.E., Suska, A,, Guo, C., Lobo, M.K., Sesack, S.R., Wolf, M.E., Nestler, E.J., Shaham, Y., Schlüter, O.M., Dong, Y. Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci 16(11): 1644-51, 2013.

Krüger, J.M., Favaro, P.D., Liu, M., Kitlinska, A., Huang, X., Raabe, M., Akad, D.S., Liu, Y., Urlaub, H., Dong, Y., Xu, W., Schlüter, O.M. Differential roles of Postsynaptic Density-93 isoforms in regulating synaptic transmission. J Neurosci 33(39): 15504-17, 2013.

Bonnet, S.A.*, Akad, D.S.*, Samaddar, T., Liu, Y., Huang, X., Dong, Y., Schlüter, O.M. Synaptic state-dependent functional interplay between Postsynaptic Density-95 and Synapse-associated Protein 102. J Neurosci 33(33):13398-409, 2013.

Ishikawa, M., Otaka, M., Huang, Y.H., Neumann, P.A., Winters, B.D., Grace, A.A., Schlüter, O.M#., Dong, Y#. Dopamine triggers heterosynaptic plasticity. J Neurosci 33(16):6759-65, 2013.

Suska, A., Lee, B.R., Huang, Y.H., Dong, Y#., Schlüter, O.M#. Selective presynaptic enhancement of the prefrontal cortex to nucleus accumbens pathway by cocaine. PNAS 110(2):713-8, 2013.

Winters, B.D.*, Krüger, J.M.*, Huang, X., Gallahe, Z.R., Ishikawa, M., Czaja, K., Krueger, J.M., Huang, Y.H., Schlüter, O.M#., Dong, Y#. Cannabinoid receptor 1-expressing neurons in nucleus accumbens. PNAS 109(40):E2717-25, 2012.

Brown, T.E., Lee, B.R., Mu, P., Ferguson, D., Dietz, D., Ohnishi, Y.N., Lin, Y., Suska, A., Ishikawa, M., Huang, Y.H., Shen, H., Kalivas, P.W., Sorg, B.A,, Zukin, R.S., Nestler, E.J., Dong, Y#., Schlüter, O.M#. A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J Neurosci 31(22):8163-74, 2011.

Huang, Y.H., Lin, Y., Mu, P., Lee, B.R., Brown, T.E., Wayman, G., Marie, H., Liu, W., Yan, Z., Sorg, B.A., Schlüter, O.M., Zukin, R.S., Dong, Y#. In vivo cocaine experience generates silent synapses. Neuron 63(1):40-7, 2009.