There are two main types of synaptic connections in the mammalian brain: excitatory glutamatergic synapses and inhibitory GABAergic synapses. The balance between excitatory and inhibitory inputs a neuron receives regulates the overall activity of neuronal networks; disruptions to this balance can cause epilepsy.
A new paper in J. Neuroscience from the Paradis lab shows that treatment of cultured neurons with the extracellular domain of the protein Sema4D causes a rapid increase (i.e. within 30 minutes) in the density of functional GABAergic synapses. Further, addition of Sema4D to neurons drives GABAergic synapse formation through a previously unappreciated mechanism: the splitting of pre-existing assemblies of the Gephyrin scaffolding protein. To our knowledge this is the fastest demonstration of synapse formation reported thus far and has significant implications for our understanding of the mechanisms of GABAergic synapse formation.
While the underlying mechanism of epileptogenesis is largely unknown, recurrent seizures emerge when there is an increase in network activity. One possible therapeutic treatment would be to restore normal network activity by increasing network inhibition. In an in vitro model of epilepsy, acute treatment with the protein Sema4D rapidly silences neuronal hyperexcitability, suggesting a possible use of Sema4D as a disease-modifying treatment for epilepsy.
Lead authors on the paper were Marissa Kuzirian, a grad student in the Neuroscience Ph.D. program, and Anna Moore, a Brandeis Neuroscience postdoctoral fellow.
