Resume: A new study reveals how the protein Gephyrin helps form synapses, providing new insights into brain connectivity. The findings could help develop treatments for conditions such as autism, epilepsy and schizophrenia.
Researchers used CRISPR-Cas9 to confirm Gephyrin’s role in the development of autonomic synapses. This breakthrough advances the understanding of synaptic mechanisms and potential therapeutic approaches.
Key Facts:
- Gephyrins role: Essential for autonomic synapse formation in the brain.
- Research method: Uses CRISPR-Cas9 on human neurons derived from stem cells.
- Therapeutic potential: Insights can lead to new treatments for neurological disorders.
Source: Colorado State University
Recently published research from Colorado State University answers fundamental questions about cellular connectivity in the brain. These questions may be useful in developing treatments for neurological disorders such as autism, epilepsy or schizophrenia.
The work, marked in the Proceedings of the National Academy of Sciences, focuses on the way neurons in the brain transmit information to each other through highly specialized subcellular structures called synapses.
These delicate structures play a key role in controlling many processes in the nervous system via electrochemical signaling. Pathogenic mutations in the genes that hinder their development can cause serious mental disorders.
Despite their important role in connecting neurons in different brain regions, the way synapses form and function is still not well understood, according to Assistant Professor Soham Chanda.
To answer that fundamental question, Chanda and his team from the Department of Biochemistry and Molecular Biology focused on a specific and important type of synapse called GABAergic. He said neuroscience researchers have long hypothesized that these synapses could form through the release of GABA and the corresponding sensing activity between two nearby neurons.
However, research in the article now shows that these synapses can develop autonomously and independently of neuronal communication, mainly due to the supportive action of a protein called Gephyrin. These findings clarify key mechanisms of synaptic formation, allowing researchers to further focus on synapse dysfunction and health treatment options.
Chanda’s team used human neurons derived from stem cells to develop a model of the brain that could rigorously test these relationships. Using a gene-editing tool called CRISPR-Cas9, they were able to genetically manipulate the system and confirm Gephyrin’s role in the synapse formation process.
“Our study shows that even if a pre-synaptic neuron does not release GABA, the postsynaptic neuron can still assemble the necessary molecular machinery primed to detect GABA,” Chanda said.
“We used a gene editing tool to remove the Gephyrin protein from neurons, largely reducing this autonomous assembly of synapses – confirming its important role regardless of neuronal communication.”
Using stem cells to advance understanding of neuron and synapse formation
Neuroscientists have traditionally used rodent systems to study these synaptic connections in the brain. While that provides a suitable model, Chanda and his team were interested in testing synapse properties in a human cellular environment that could ultimately be more easily translated into treatments.
To achieve this, his team grew human stem cells to form brain cells that could mimic the properties of human neurons and synapses. They then performed extensive high-resolution imaging of these neurons and monitored their electrical activities to understand synaptic mechanisms.
Chanda said several mutations in the Gephyrin protein have been linked to neurological disorders such as epilepsy, which alter neuronal excitability in the human brain. That makes understanding its fundamental cellular function an important first step toward treatment and prevention.
“Now that we better understand how these synaptic structures interact and organize, the next question will be to elucidate how defects in their relationships can lead to disease and to identify the ways in which one can predict or intervene in that process,” he said.
About this genetics and neurology research news
Author: Joshua Rhoten
Source: Colorado State University
Contact: Joshua Rhoten – Colorado State University
Image: The image is credited to Neuroscience News
Original research: Closed access.
“Gephyrin promotes the autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release” by Soham Chanda et al. PNAS
Abstract
Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release
Synapses containing γ-aminobutyric acid (GABA) are the primary centers for inhibitory neurotransmission in our nervous system. It is unclear how these synaptic structures form and tune their postsynaptic machinery to presynaptic terminals.
Here we monitored the cellular distribution of several GABAergic postsynaptic proteins in a purely glutamatergic neuronal culture derived from human stem cells, which contains virtually no vesicular GABA release.
We found that several GABAa receptor (GABAaR) subunits, postsynaptic scaffolds, and key cell adhesion molecules can reliably coaggregate and colocalize on even GABA-deficient subsynaptic domains, but remain physically separated from glutamatergic counterparts.
Genetic deletions of both Gephyrin and a Gephyrin-associated guanosine di- or triphosphate (GBP/GTP) exchange factor Collybistine severely disrupted the co-assembly of these postsynaptic compositions and their proper apposition with presynaptic inputs.
Gephyrin-GABAaR clusters, developed in the absence of GABA transmission, could then be activated and even enhanced by a delayed supply of vesicular GABA. Thus, the molecular organization of GABAergic postsynapses may initiate via a GABA-independent but Gephyrin-dependent intrinsic mechanism.