Tiam1 is Critical for Glutamatergic Synapse Structure and Function in the Hippocampus.

Mounting evidence suggests numerous glutamatergic synapse subtypes exist in the brain, and that these subtypes are likely defined by unique molecular regulatory mechanisms. Recent work has identified substantial divergence of molecular composition between commonly studied Schaffer collateral synapses and perforant path-dentate gyrus (DG) synapses of the hippocampus. However, little is known about the molecular mechanisms that may confer unique properties to perforant path-DG synapses. Here we investigate whether the RhoGEF (Rho guanine-nucleotide exchange factor) protein Tiam1 plays a unique role in the regulation of glutamatergic synapses in dentate granule neurons using a combination of molecular, electrophysiological, and imaging approaches in rat entorhino-hippocampal slices of both sexes. We find that inhibition of Tiam1 function in dentate granule neurons reduces synaptic AMPA receptor function and causes dendritic spines to adopt an elongated filopodia-like morphology. We also find that Tiam1's support of perforant path-DG synapse function is dependent on its GEF domain and identify a potential role for the auto-inhibitory PH domain of Tiam1 in regulating Tiam1 function at these synapses. In marked contrast, reduced Tiam1 expression in CA1 pyramidal neurons produced no effect on glutamatergic synapse development. Together, these data identify a critical role for Tiam1 in the hippocampus and reveal a unique Tiam1-mediated molecular program of glutamatergic synapse regulation in dentate granule neurons.SIGNIFICANCE STATEMENT Several lines of evidence independently point to the molecular diversity of glutamatergic synapses in the brain. Rho guanine-nucleotide exchange factor (RhoGEF) proteins as powerful modulators of glutamatergic synapse function have also become increasingly appreciated in recent years. Here we investigate the synaptic regulatory role of the RhoGEF protein Tiam1, whose expression appears to be remarkably enriched in granule neurons of the dentate gyrus. We find that Tiam1 plays a critical role in the development of glutamatergic perforant path-dentate gyrus synapses, but not in commonly studied in Schaffer collateral-CA1 synapses. Together, these data reveal a unique RhoGEF-mediated molecular program of glutamatergic synapse regulation in dentate granule neurons.