The balance between excitation and inhibition in neuronal networks (E/I balance) regulates overall network function; disruptions to this balance are thought to underlie neurodevelopmental disorders such as Autism Spectrum Disorders and epilepsy. To understand how E/I balance is established and regulated, it is first necessary to define the genes and signaling pathways that instruct excitatory and inhibitory synaptic connections between neurons. During the last funding cycle, we identified a novel ligand-receptor pair, Sema4D and PlexinB1, which bi-directionally regulates GABAergic synapse formation on an unprecedentedly fast time-scale. We also discovered that Sema4D could be used to rapidly (within 2 hrs) drive inhibition and suppress neuronal hyperactivity in organotypic hippocampal slice cultures. Intriguingly, our preliminary data also demonstrate that in vivo application of Sema4D can reduce seizure severity in a mouse model of epilepsy, consistent with a Sema4D-dependent increase in inhibition in the nervous system of these animals. In addition, preliminary studies indicate that a relatively short time window of Sema4D treatment (e.g. 2 hrs) promotes the formation of functional GABAergic synapses that persist for days. The overall goal of this proposal is to elucidate how the Sema4D-dependent signaling pathway acts to re-set E/I balance in neuronal circuits through the promotion of GABAergic, inhibitory synapse development. In particular, we propose a set of experiments to understand how Sema4D and PlexinB1 mediate the rapid formation of GABAergic synapses using a combination of molecular biology, biochemistry, electrophysiology, and cutting-edge, time-lapse microscopy both in vitro and in vivo. Further, this Sema4D-dependent, rapid formation of GABAergic synapses leads us to hypothesize that, in the long term, harnessing the synaptogenic potential of Sema4D/PlexinB1 signaling could translate into an effective therapeutic for neurological conditions in which disruptions to the E/I balance is a salient feature.

Public Health Relevance

Statement Neurological disorders such as epilepsy are due to a disruption in the proper balance of excitatory and inhibitory synapses such that there is too much excitation. Our laboratory has discovered that the protein Sema4D causes new inhibitory synapses to form within a few hours. Our proposal aims to test the hypothesis that Sema4D, or molecules like it, might restore the balance of excitation and inhibition in brain and therefore be a useful therapeutic for individuals with seizure disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065856-07
Application #
9147485
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2010-08-01
Project End
2019-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
7
Fiscal Year
2016
Total Cost
$353,931
Indirect Cost
$135,181
Name
Brandeis University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02453
Moore, Anna R; Richards, Sarah E; Kenny, Katelyn et al. (2018) Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits. Elife 7:
Royer, Leandro; Herzog, Josiah J; Kenny, Katelyn et al. (2018) The Ras-like GTPase Rem2 is a potent inhibitor of calcium/calmodulin-dependent kinase II activity. J Biol Chem 293:14798-14811
McDermott, Jacqueline E; Goldblatt, Dena; Paradis, Suzanne (2018) Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus. Mol Cell Neurosci 92:50-66
Acker, Daniel W M; Wong, Irene; Kang, Mihwa et al. (2018) Semaphorin 4D promotes inhibitory synapse formation and suppresses seizures in vivo. Epilepsia 59:1257-1268
Herzog, Josiah J; Deshpande, Mugdha; Shapiro, Leah et al. (2017) TDP-43 misexpression causes defects in dendritic growth. Sci Rep 7:15656
Kenny, Katelyn; Royer, Leandro; Moore, Anna R et al. (2017) Rem2 signaling affects neuronal structure and function in part by regulation of gene expression. Mol Cell Neurosci 85:190-201
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Ghiretti, Amy E; Paradis, Suzanne (2014) Molecular mechanisms of activity-dependent changes in dendritic morphology: role of RGK proteins. Trends Neurosci 37:399-407
Ghiretti, Amy E; Moore, Anna R; Brenner, Rebecca G et al. (2014) Rem2 is an activity-dependent negative regulator of dendritic complexity in vivo. J Neurosci 34:392-407
Raissi, Aram J; Scangarello, Frank A; Hulce, Kaitlin R et al. (2014) Enhanced potency of the metalloprotease inhibitor TAPI-2 by multivalent display. Bioorg Med Chem Lett 24:2002-7

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