Making new synapses with Sema4D

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.

Screen Shot 2013-05-26 at 5.03.05 PMWhile 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.

Glutamatergic and GABAergic

Can you say that three times fast? Glumatergic (excitatory) synapses respond to the neurotransmitter  glutamate, and GABAergic (inhibitory) synapses respond to gamma-aminobutyric acid (GABA).  GABA is formed by decarboxylating glutamate. These are the “workhorse” neurotransmitters in the brain.

Neuroscience grad stduent Marissa Stearns Kuzirian and Assistant Professor of Biology Suzanne Paradis discuss what’s known about  how GABAergic synapses form, and the relationships to the previously better-studied formation of glutamergic synapses, in a new review entitled  “Emerging themes in GABAergic synapse development” in Progress in Neurobiology.

Neurons branch out: a role for Rem2

The development of the central nervous system involves a series of complex yet tightly-regulated processes, including the formation of synapses, the sites of communication between neurons, and the morphogenesis of the dendritic arbor, where the majority of synaptic contacts occur. Importantly, the misregulation of these processes is a hallmark of many neurodevelopmental disorders, including autism and mental retardation. However, the molecular mechanisms that underlie these structural and functional changes remain largely obscure.

The lab of Prof. Suzanne Paradis at Brandeis is working to identify and characterize molecules that regulate neural development in the rodent hippocampus. A recently accepted manuscript at Developmental Neurobiology by Brandeis Neurocience Ph.D. student Amy Ghiretti and Dr. Paradis uses RNAi in primary hippocampal cultures to identify novel roles for the GTPase Rem2 in several neurodevelopmental processes. The RNAi-mediated decrease of Rem2 leads to the formation of fewer excitatory synapses, and also results in increased dendritic complexity, suggesting that Rem2 functions normally to promote synapse formation and to inhibit dendritic branching. Additionally, the binding of Rem2 to the calcium-binding protein calmodulin was identified as a key interaction that distinguishes the signaling pathways through which Rem2 mediates synapse development and dendritic branching. Overall, this study identifies Rem2 as a novel regulator of several neurodevelopmental processes, and importantly, suggests that Rem2 regulates excitatory synapse development and dendritic morphology via separable and distinct signaling pathways.

Figure: Neurons in which Rem2 protein expression has been decreased by RNAi (top) show increased dendritic branching compared to control neurons (bottom), suggesting Rem2 acts to inhibit branching

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