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

Abstract

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.

Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease

“…The report that a same Neuroligin4 mutation can generate either ID or high-level ASD supports such subtle changes (67). Similarly, some protein complexes may integrate only a given form of a protein, as it is the case for TIAM1 in glutamatergic synapses from entorhinal cortex (39).…”

Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization

“…Sanger sequencing confirmation could not be performed. De novo frameshift deletions in TIAM1 have been reported in three cases of autism thus far (Kosmicki et al, 2017), and mouse models investigating this gene has shown it plays a role in learning and memory in the hippocampus (Kojima et al, 2019; Rao, Kay, & Herring, 2019). The inframe insertion occurs in a well conserved region of the gene (CCR percentile = 96.35) (Havrilla, Pedersen, Layer, & Quinlan, 2019) while the gene is predicted to be intolerant of LoF variation (pLI = 0.96), it seems to tolerate missense variation (Zmiss = 1.7).…”

An optogenetic method for investigating presynaptic molecular regulation

“…Instead, cultured neurons form indiscriminate synaptic connections regardless of their endogenous connections or cell type. The hippocampus, for example, has discrete regions of neuronal subtypes such as CA3 and CA1 pyramidal neurons and dentate granule neurons, and it has been increasingly appreciated that there is pathway-specific regulation that functionally differentiates these synapses 5 , 18 – 21 . Our novel approach allows for keeping the endogenous circuitry of synapses intact by utilizing hippocampal slices.…”

“…Highly specific, efficient, and quantitative methods currently exist for studying the influence of postsynaptic proteins on glutamatergic synapse function in the mammalian central nervous system. For example, viral and biolistic approaches may be used to restrict genetic manipulations to postsynaptic neurons, and the consequences of such manipulations may be measured by electrophysiological recordings from individual transduced/transfected postsynaptic neurons during electrical stimulation of unmodified presynaptic neurons 1 – 5 . However, comparable methods are sorely lacking for the study of proteins regulating presynaptic glutamatergic synapse function.…”