Camin Dean
Synaptic Dysfunction
Dr. Camin Dean
Group Leader
Hufelandweg 14
10117  Berlin

camin.dean@dzne.de
 +49 30 450-539708

Areas of investigation/research focus

Memory encoding and forgetting require strengthening and weakening of synapses - the sites of communication between nerve cells. Synapse weakening is also a common early feature of neurodegenerative diseases. This leads to memory loss when it occurs in the hippocampus, a high level brain area that is first and most affected by Alzheimer’s disease. Our team aims to identify and manipulate molecules that strengthen or weaken synapses, to counteract neurodegenerative disease. To do this, we use a combination of live imaging, nanoscopy, electrophysiology, biochemistry, genomics, and behavioral techniques.

Recently, we found that Syt3, a calcium sensor for membrane fusion, internalizes AMPA receptors to weaken synapses and promote forgetting (Awasthi et al. Science 2019). Knockout of Syt3 abolishes long-term depression (weakening) of synapses, promotes longer-lasting potentiation (strengthening) of synapses, and blocks forgetting in mice. Perturbing Syt3 function may prevent or reverse memory loss in Alzheimer’s disease. We are also using specialized natural behavior tests to quantify forgetting and the importance of synapse stability in maintaining or modifying memories.

In another line of research, we discovered that TRPV1, a channel activated by heat and endocannabinoids, is expressed in OLM neurons in the hippocampus, where it promotes their excitatory innervation (Hurtado-Zavala et al. Nat. Comm. 2017). These neurons are highly susceptible to degeneration, which causes memory loss. Excitatory innervation of OLM neurons is dramatically reduced in TRPV1 knockouts, which impairs long-term potentiation of synapse strength. We are investigating the function of TRPV1 and OLM neurons in sharp wave ripples - brain waves that occur during sleep, and are necessary to consolidate and preserve new memories.

We also recently found that Syt4, on BDNF vesicles, promotes their capture at active synapses in the hippocampus (Bharat et al. Cell Rep., 2017), and regulates BDNF release to keep synapse strength within an optimal range for normal learning and memory (Dean et al. Nat. Neurosci. 2009). We further found that BDNF is taken up by astrocytes, and increases their territory. This may be important to protect synapses in the striatum - the brain area first and most affected by Huntington’s and Parkinson’s disease, which relies on BDNF import from the cortex - from weakening and degeneration.

Memory and associated dementia are likely multi-factorial, encompassing a pattern of gene expression, rather than individual “memory” molecules. We aim to identify the “memory signature”, necessary for memory encoding (synapse strengthening) or forgetting (synapse weakening), in both brain slices and hIPSC-derived neuronal networks. In a complementary approach, synaptic engrams in brain and neuronal organoids are identified using fluorescent reporters of synapse formation. This information will allow us to discover cognition-enhancing compounds targeting the memory signature.

Key Publications

Awasthi A, Ramachandran B, Ahmed S, Benito E, Shinoda Y, Nitzan N, Heukamp A, Rannio S, Martens H, Barth J, Burk K, Wang YT, Fischer A, Dean C. Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting. Science. 2020 Jan 04; 363:6422. doi: 10.1126/science.aav1483
Bharat V, Siebrecht M, Burk K, Ahmed S, Reissner C, Kohansal-Nodehi M, Steubler V, Zweckstetter M, Ting JT, Dean C. Capture of dense core vesicles at synapses by JNK-dependent phosphorylation of synaptotagmin-4. Cell Rep. 2017 Nov 21; 21:2118-2133. doi: 10.1016/j.celrep.2017.10.084
Hurtado-Zavala JI, Ramachandran B, Ahmed S, Halder R, Bolleyer C, Awasthi A, Stahlberg MA, Wagener RJ, Anderson K, Drenan RM, Lester HA, Miwa JM, Staiger JF, Fischer A, Dean C. TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus. Nat Commun. 2017 Jul 19; 19:8:15878. doi: 10.1038/ncomms15878
Dean C, Liu H, Dunning FM, Chang PY, Jackson, MB, Chapman, ER. Synaptotagmin-IV modulates synaptic function and LTP by regulating BDNF release. Nature Neurosci. 0009 Jan 01; 12:767-76. doi: 10.1038/nn.2315
Dean C, Scholl FG, Choih J, DeMaria S, Berger J, Isacoff E, Scheiffele P. Neurexin mediates the assembly of presynaptic terminals. Nature Neurosci. 0003 Jul 01; 6:708-16. doi: 10.1038/nn1074

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