Synapses are specialized sites of cell-cell contact that mediate communication between neurons in the nervous system. Much remains to be discovered about the molecular mechanisms that underlie formation of these critical structures in the mammalian central nervous system. While recent advances have contributed to our understanding of excitatory synapse formation, the processes that mediate inhibitory synapse formation remain poorly defined. In addition, it is hypothesized that aberrant synapse formation and function contributes to neurological disorders such as mental retardation, autism spectrum disorders and epilepsy. To appreciate how synapse dysfunction contributes to these widespread neurological impairments, it is important to first understand how synapses are formed, maintained, and function in the non-pathological state. To this end, we developed a novel, forward genetic RNA interference (RNAi)-based screen in cultured hippocampal neurons that has identified new molecules required for synapse formation. Using this technique, we discovered that RNAi-mediated knockdown of a class 4 Semaphorin, Sema4D, led to a decrease in the density of inhibitory synapses without an apparent effect on excitatory synapse formation. Thus, Sema4D is one of only a few molecules identified thus far that preferentially regulates inhibitory synapse formation. Further, Sema4D appears to be playing a specific role in assembling the postsynaptic specialization at inhibitory synapses. Therefore, understanding the mechanism of action of Sema4D in this process promises to yield key insights into the assembly of inhibitory synapses in the mammalian central nervous system.

Public Health Relevance

Numerous studies now point to defects in synapse formation as a possible cause for neurological disorders such as autism, mental retardation, and epilepsy. To appreciate how aberrant synapse formation contributes to these widespread neurological impairments, it is important to first understand how synapses are formed, maintained, and function in the non-pathological state. Thus, in-depth study of the mechanism of action of Sema4D in synapse formation as outlined in this proposal has the potential to yield important insights into the underlying cause of some of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brandeis University
Schools of Arts and Sciences
United States
Zip Code
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
Steinmetz, Celine C; Tatavarty, Vedakumar; Sugino, Ken et al. (2016) Upregulation of ?3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway. Cell Rep 16:2711-2722
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

Showing the most recent 10 out of 16 publications