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.
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.
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