Synaptopathy
Prof. Dr. Craig Curtis Garner
Group Leader
Charitéplatz 1
10117 Berlin

craig-curtis.garner@dzne.de
 +49 30 450-539166

Areas of investigation/research focus

The work of my group is focused on understanding the molecular, cellular and physiological mechanisms regulating the dynamic assembly and function of vertebrate CNS synapses. Much of the early work of my group was designed to identify and characterize core components of excitatory synapses and define which roles they play in the regulated release of neurotransmitters and the dynamic recruitment, retention and function of postsynaptic glutamate receptors. These studies have shown that cellular programs that control the dynamic exchange and degradation of pre- and postsynaptic proteins govern the formation, maintenance and integrity of synapses.  Ongoing work in the lab is focused on how genetic and/or environmental insults adversely influence these programs, leading to synapse dysfunction and/or neuronal degeneration.

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Our program is primarily focused on translating knowledge acquired on the functional assembly and integrity of synapses to the development of pharmacotherapies to restore cognitive impairment in both neurodevelopmental and neurodegenerative disorders.  Examples include efforts to develop drugs that normalize cognitive function in individuals with Down syndrome (DS), Alzheimer’s disease (AD) and Phelan Mcdermid syndrome (PMS).  Regarding the former, our studies have shown that excessive inhibitory tone within neuronal circuits can lead to cognitive impairment in mouse models of DS, a condition that can be reversed by administering low doses of a variety of GABAA receptor antagonists.  Intriguingly, excessive inhibitory tone also appears to contribute to cognitive dysfunction in patients with AD and sleep disorders. To test this concept, we founded a small biotech company, “Balance Therapeutics Inc.” in 2009.  This organization recently initiated a phase Ib/II clinical trial (Compose 21) to assess whether modulating inhibitory tone can restore cognitive function in young adults with DS and as well as different sleep disorders (Arise). Our studies have also found that zinc dependent signaling at synapses, required for normal synaptic plasticity mechanisms, network function and cognitive performance, is impaired in mouse models of with PMD and AD.  Pre-clinical studies using zinc supplementation indicate that this strategy could be effective in normalizing behavior and cognition in these patients.

Key Publications

Richard J. Reimer, Katharina Schneider, Sergio Leal-Ortiz, Carolina Montenegro-Venegas, Sally A. Kim, Loren C. Garner, Eckart D. Gundelfinger, Richard J. Reimer, Craig C. Garner. Bassoon Controls Presynaptic Autophagy through Atg5. Neuron. 2017 Feb. 21; 93:897-913.e7. doi: 10.1016/j.neuron.2017.01.026
Waites CL, Leal-Ortiz SA, Okerlund N, Dalke H, Fejtova A, Altrock WD, Gundelfinger ED, Garner CC. Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation. EMBO J. 2013 Apr. 03; 32:954-69. doi: 10.1038/emboj.2013.27
Adorno M, Sikandar S, Mitra SS, Kuo A, …, Garner CC, Clarke MF. Trisomy of Usp16 contributes to stem cell and senescence defects in somatic tissues of Down syndrome mice. Nature. 2012 Jan. 01; 501:380-4. doi: 10.1038/nature12530
Arons MH, Thynne CJ, Grabrucker AM, Li D, Schoen M, Cheyne JE, Boeckers TM, Montgomery JM, Garner CC. Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci. 2012 Oct. 24; 32:14966-78. doi: 10.1523/JNEUROSCI.2215-12. 2012
Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 2007 Apr. 01; 10:411-33.

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