Summary: A new study reveals how the protein Gephyrin helps form synapses, providing new insights into brain connectivity. The findings could help develop treatments for disorders such as autism, epilepsy and schizophrenia.
The researchers used CRISPR-Cas9 to confirm Gephyrin’s role in autonomic synapse development. This breakthrough improves understanding of synaptic mechanisms and potential therapeutic approaches.
Key facts:
- The role of Gephyrin: Essential for the formation of autonomic synapses in the brain.
- Research method: Using CRISPR-Cas9 on human stem cell-derived neurons.
- Therapeutic potential: Insights may lead to new treatments for neurological disorders.
source: Colorado State University
Newly published research from Colorado State University answers fundamental questions about cellular connectivity in the brain that could be useful in developing treatments for neurological diseases such as autism, epilepsy or schizophrenia.
The work highlighted in Proceedings of the National Academy of Sciences, focuses on how neurons in the brain transmit information to each other through highly specialized subcellular structures called synapses.
These delicate structures are key to controlling many processes in the nervous system through electrochemical signaling, and pathogenic mutations in genes that damage their development can cause severe mental disorders.
Despite their important role in connecting neurons in different areas of the brain, how synapses form and function is still not well understood, said assistant professor Soham Chanda.
To answer this fundamental question, Chanda and his team in 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 may form due to the release of GABA and corresponding sensory activity between two neurons in close proximity.
However, research in the paper now shows that these synapses can begin to develop autonomously and separately from this neuronal communication, mainly due to the scaffolding action of a protein called Gephyrin. These findings elucidate key mechanisms of synaptic formation, which may allow researchers to further focus on synapse dysfunction and health treatment options.
Chanda’s team used human neurons derived from stem cells to develop a brain model 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 process of synapse formation.
“Our study shows that even if the presynaptic neuron does not release GABA, the postsynaptic neuron can still assemble the necessary molecular mechanisms primed to sense GABA,” Chanda said.
“We used a gene-editing tool to remove the protein Gephyrin from neurons, which largely reduced this autonomous assembly of synapses—confirming its important role independently of neuronal communication.”
Using stem cells to better understand the formation of neurons and synapses
Neuroscientists have traditionally used rodent systems to study these synaptic connections in the brain. While this provides a suitable model, Chanda and his team are interested in testing the properties of synapses in a human cellular environment that may ultimately be more easily translated into treatments.
To achieve this, his team cultivated human stem cells to form brain cells that could mimic the properties of human neurons and synapses. They then conducted extensive high-resolution imaging of these neurons and tracked their electrical activities to understand synaptic mechanisms.
Chanda said several mutations in the Gephyrin protein are linked to neurological disorders such as epilepsy, which alter neuronal excitability in the human brain. This makes understanding its underlying cellular function an important first step toward treatment and prevention.
“Now that we better understand how these synaptic structures interact and organize themselves, the next question will be to elucidate how defects in their relationships can lead to disease and to identify ways in which one can predict or intervene in this process,” he said.
About this genetics and neuroscience research news
Author: Joshua Rothen
source: Colorado State University
Contact: Joshua Rotten – Colorado State University
Image: Image credit: Neuroscience News
Original research: Closed access.
“Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release” by Soham Chanda et al. PNAS
Summary
Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release
Synapses containing γ-aminobutyric acid (GABA) represent the main centers for inhibitory neurotransmission in our nervous system. It is not clear how these synaptic structures form and align their postsynaptic mechanisms with presynaptic terminals.
Here, we observed the cellular distribution of several GABAergic postsynaptic proteins in a purely glutamatergic neuronal culture derived from human stem cells, which has virtually no vesicular release of GABA.
We found that several GABAA receptor (GABAAR) subunits, postsynaptic scaffolds, and basic cell-adhesion molecules can reliably coaggregate and colocalize even in GABA-deficient subsynaptic domains, but remain physically separated from glutamatergic counterparts.
Genetic deletions of both Gephyrin and the Gephyrin-related guanosine di- or triphosphate (GDP/GTP) exchange factor Collybistin severely impair the co-assembly of these postsynaptic assemblies and their proper placement with presynaptic inputs.
Gephyrin-GABAAR clusters developed in the absence of GABA transmission can subsequently be activated and even potentiated by delayed vesicular GABA supply. Thus, the molecular organization of GABAergic postsynapses may be initiated by a GABA-independent but Gephyrin-dependent intrinsic mechanism.
