The development of the nervous system is associated with the generation of excess neuronal synapses that is followed by their removal, a process known as synaptic pruning. Depending on the area of the brain, up to 70% of pre-formed synapses are lost during developmental circuit refinement. Why are so many synapses lost, what determines which synapses are eliminated, what are the molecular mechanisms involved, and what are the consequences of not getting it right? Appropriate synaptic pruning appears to be required for the strengthening of remaining synapses and is critical for normal brain development. In animal models, aberrations of synaptic pruning lead to impaired brain circuit maturation and dysfunctional connectivity. In human brain imaging and post-mortem studies, the reduction of brain volume and reduced density of dendritic spines in schizophrenia is suggestive of over-pruning, whereas increased brain volume and dendritic spine densities may indicate under-pruning in autism.

Unfortunately, the risks underlying these circuit disorders and the reason why synaptic pruning is required to achieve the final connectome is currently poorly understood. For a long time synaptic pruning has been seen as a neuron-autonomous process. However, recent studies revealed that unnecessary synapses may be phagocytosed by resident immune cells – microglia. In mouse models, microglia cells are recruited to the maturing brain regions by neuronal chemotactic protein fractalkine and eliminate synapses in a complement-dependent manner. But how do these systems function to selectively drive the elimination of some synapses over others?

For microglia to discriminate between subsets of synapses that need to be removed or maintained there must be molecular signal(s) that are exposed on the surface of the synapse to trigger or inhibit microglial recognition and engulfment. We aim to define molecular signaling pathways that drive this highly specific pruning of unnecessary synapses. For this we use both ex vivo tissue cultures and genetically modified mouse lines. In collaboration with Dr. Carsten Schultz (EMBL) we are developing novel chemistry tools for rapid, selective, and sensitive labeling of synaptic surface molecules. High resolution fluorescent microscopy of developing circuits is supplemented with electrophysiology studies and animal behaviour experiments. We intend to define synapses destined for elimination in vitro and thereafter in vivo and to elucidate their molecular signatures, giving first direct insights into the molecular cascades that are required for developmental synaptic pruning in maturing circuits of the brain.

 

Group members

 urte neniskyte

Team leader

Dr. Urtė Neniškytė

 

 avinash 

 Postdoctoral researcher

Dr. Avinash Parimisetty

 

 gyvunu technike viktorija kralikiene 

 Animal technician

Viktorija Kralikienė

 

 Daina Pamedytytė

PhD sudent

Daina Pamedytytė

 

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PhD sudent

Lina Saveikytė

 

 

ugne 

PhD student

Ugnė Kulešiūtė

 

 

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MSc student

Kristina Jevdokimenko

 

kornelija

MSc student

Kornelija Vitkutė

 

arnas

MSc student

Arnas Kunevičius

 

 

simona

BSc

Simona Bartkevičiūtė

 

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BSc

Eimina Dirvelytė

PhD student

Gintarė Urbonaitė

 

 

PhD student

Dovydas Gabrielaitis

Contacts

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tel. +370 (5) 223 4437

Collaborators

Dr. Cornelius Gross, Mouse Biology Unit, European Molecular Biology Laboratory, Monterotondo, Italy

UAB Oxipit, Vilnius, Lietuva

Prof. Guy C. Brown, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom

Dr. Etienne Herzog, CNRS Researcher, Interdisciplinary Institute for NeuroScience, Université de Bordeaux, Bordeaux, France

Projects

LIPSYNING, Marie Sklodowska Curie Individual Fellowship, Horizon 2020, 2016-2019

IBRO Return Home Fellowship, 2017-2019

Publications

Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, Exiga M, Vadisiute A, Raggioli A, Schertel A, Schwab Y, Gross CT. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat
Commun. 2018;9(1):1228.

Weinhard L, Neniskyte U, Vadisiute A, Di Bartolomei G, Aygün, N, Riviere L, Zonfrillo F, Dymecki S, Gross C. Sexual dimorphism in microglia and synapses during mouse postnatal development. Dev Neurobiol. 2017

Neniskyte U & Gross C. The errant gardener: glia -dependent developmental synaptic pruning and psychiatric disorders. Nat Rev Neurosci. 2017 Sep 21.

Neniskyte U, Fricker M, Brown GC. Amyloid β induces microglia to phagocytose neurons via activation of protein kinase Cs and NADPH oxidase. Int J Biochem Cell Biol. 2016 Dec;81(Pt B):346-355.

Neniskyte U, Vilalta A, Brown GC. Tumour necrosis factor alpha-induced neuronal loss is mediated by microglial phagocytosis. FEBS Lett. 2014 Aug 25;588(17):2952-6.

Neher JJ, Neniskyte U, Hornik T, Brown GC. Inhibition of UDP/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo. Glia. 2014 Sep;62(9):1463-75.

Hornik TC, Neniskyte U, Brown GC. Inflammation induces multinucleation of Microglia via PKC inhibition of cytokinesis, generating highly phagocytic multinucleated giant cells. J Neurochem. 2014 Mar;128(5):650-61.

Neniskyte U & Brown GC. Analysis of microglial production of reactive oxygen and nitrogen species. Methods Mol Biol. 2013;1041:103-11.

Neniskyte U & Brown GC. Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid β. J Neurochem. 2013 Aug;126(3):312-7.

Neher JJ, Neniskyte U, Brown GC. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front Pharmacol. 2012 Feb 28;3:27.

Neniskyte U, Neher JJ, Brown GC. Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia. J Biol Chem. 2011 Nov 18;286(46):39904-13.

Neher JJ, Neniskyte U, Zhao JW, Bal-Price A, Tolkovsky AM, Brown GC. Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol. 2011 Apr 15;186(8):4973-83.