With its stunning views and stunning stature, the Golden Gate Bridge certainly deserves its title as one of the modern wonders of the world. Its elegant art deco style and iconic towers offer visitors a unique opportunity in life to take amazing photographs. The Golden Gate, which stretches for almost 2 kilometers, serves as a critical gateway, facilitating the exchange of ideas, commodities and people.
Although they are not of the same magnificent scale, our brains have similar gateways to connect neurons. These tiny compartments, called synapses, allow for the dynamic exchange of information and the formation of neural circuits. To build these circuits, developing neurons must first follow specific guiding directions, traveling through the brain until they find their right partners. This process is largely important for the cerebral cortex, which consists of six functionally and anatomically different layers. Although the crust has been extensively studied, little is known about the precise molecular mechanisms that lead to the specificity of the synapse in its layers. This is especially true for a specialized class of neurons called inhibitory interneurons (IN), which usually make local connections with only one or two layers. Discovering the molecules at play would foster an understanding of the formation of cortical inhibitory circuits.
In a recent publication in the journal Scientific advances, Max Planck’s Taniguchi Laboratory in Florida has shed light on a new mechanism for inhibiting synapse specificity in the cortex. By identifying a novel role for the IgSF11 cell adhesion molecule, MPFI scientists have found that the protein mediates layer-specific synaptic orientation in cortical chandelier (CHC) cells.
“Our laboratory specializes in the study of cortical interneurons and the formation of inhibitory circuits,” describes Dr. Hiroki Taniguchi, Ph.D. and leader of the research group at Max Planck Florida. “Chandelier cells, one of our favorite subtypes of interneurons, have been shown to express unique genetic markers and only innervate certain layers of the cortex (ChCs critically control the generation of spikes in major cortical neurons and have been implicated in the pathology of brain disorders such as schizophrenia and epilepsy.) We decided that this cell-type model would be the perfect place to begin our search for molecules that confer a layer-specific synapse. “
MPFI scientists began their research using single-cell RNA sequencing to genetically examine the INs of genes unique to an individual subtype. They found a selective set of genes in an intriguing category known as cell adhesion molecules, or CAMs. One CAM in particular, IgSF11, was highly enriched in ChC compared to other IN subtypes.
“Our IN genetic screening is where we first encountered IgSF11,” explains Yasufumi Hayano, Ph.D., first author of the publication and a research scientist at Taniguchi Lab. “We were looking for subtype-specific genes that encoded proteins on the cell surface, thinking that those expressed on the outside of neurons would be the perfect candidate to mediate a specific synapse interaction.”
CAMs form a diverse group of structural proteins. Often considered a biological glue, CAMs are expressed on the outside of neurons and interact in large complexes, facilitating interactions between cells. The bridge-shaped complex they form provides stability for newly formed synapses and aids in the adhesion and communication of cells. One category of CAMs, called homophilic CAMs, only interacts with other CAMs that are identical to themselves and theorized to have the ability to mediate the specificity of synapse formation.
After identifying IgSF11 as a homophilic CAM, the MPFI team looked for IgSF11 expression in neurons in the upper half of the 2/3 layer of the cortex innervating ChCs, arguing that the expression should occur on both sides for a homophilic CAM interaction. Using in situ fluorescent hybridization (FISH), the researchers found robust IgSF11 expression in both ChCs and target neurons residing within layer 2/3 of the crust, but not in other layers, providing solid evidence. that IgSF11 interaction is important in ChC synapse specificity.
Next, Taniguchi’s laboratory evaluated the functional role of IgSF11 in the formation of ChC synapses by removing IgSF11 from the brain and examining the changes. To analyze whether IgSF11 was functionally necessary only in ChCs or both target ChCs and cortical neurons, the team had to develop a strategy that would allow selective elimination of IgSF11. To achieve this, MPFI scientists generated KS IgSF11 mice and transplanted fluorescently identified KC ChC into wild-type host animals. KO ChCs showed a significant reduction in both the size and number of synaptic buttons. Supporting the hypothesis that IgSF11 confers its specificity through homophilic interaction, transplantation of WC ChCs into the brain of IgSF11 KO mice resulted in the same reduction. Overall, IgSF11 appears to be strongly involved in the development of ChC synaptic buds and morphological differentiation.
Collaborations with the MPFI electron microscopy core and the Kwon laboratory delved into the functional consequences of KO IgSF11. Analysis of infrastructures using high-magnification MS revealed that the few remaining synaptic buttons in KO ChC did not differentiate correctly and showed deficits in synaptic transmission. Supporting these data, optogenetic-assisted electrophysiology of IgSF11 KO mice demonstrated additional deficits in synaptic transmission.
“A challenge of working with Chandelier cells is that they are difficult to manipulate genetically using traditional methods,” explains Dr. Hayano. “To overcome this, we devised a new virus-based strategy using adeno-associated viruses to administer IgSF11, a difficult-to-express protein, to cells of interest.”
The MPFI team used their AAV viral strategy to investigate whether IgSF11 expressed in neurons of different cortical layers other than layer 2/3 could artificially induce synapse formation with ChC. By transducting layer V neurons with IgSF11, they discovered numerous ectopic synapses formed between these cells and spider cells, a phenomenon that would not occur under normal circumstances.
“IgSF11 is the first cell adhesion molecule identified that directly mediates the interneuron subtype, the specific formation of synapse layer in the cortex,” notes Dr. Taniguchi. “Further elucidating the molecular mechanisms surrounding the inhibitory circuit as a whole may reveal a similar pattern in other subtypes of different interneurons and help to break down how inhibitory circuits are formed. Our work can provide a useful entry point for understanding the inhibitory circuit.” ‘etiology of neurodevelopmental disorders caused by deficiency of circuits in interneuron subtypes. ”
Yasufumi Hayano et al, IgSF11 homophilic adhesion proteins promote layer-specific synaptic assembly of the cortical interneuron subtype, Scientific advances (2021). DOI: 10.1126 / sciadv.abf1600
Max Planck Florida Institute for Neuroscience
Citation: Molecular bridge mediates the specificity of inhibitory synapses in the cortex (2021, July 14) retrieved July 14, 2021 from https://medicalxpress.com/news/2021-07-molecular-bridge-inhibitory- synapse-specificity.html
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