Summary: A new study reveals how the protein Gephyrin helps form synapses and provides new insights into brain wiring. The findings could help develop treatments for disorders such as autism, epilepsy and schizophrenia.
The researchers used CRISPR-Cas9 to confirm the role of Gephyrin in the development of autonomic synapses. This breakthrough improves understanding of synaptic mechanisms and potential therapeutic approaches.
Key facts:
- Gefyrin’s role: Necessary for the formation of autonomic synapses in the brain.
- Research method: Applied CRISPR-Cas9 to human stem cell-derived neurons.
- Therapeutic potential: The findings could 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 disrupt their development can cause serious mental disorders.
Despite their important role in connecting neurons in different areas of the brain, the way synapses form and function is still not well understood, said Assistant Professor Soham Chanda.
To answer this crucial 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 sensing activity between two neurons in close proximity.
However, the research in this paper now shows that these synapses can begin to develop autonomously and independently of neuronal communication, largely thanks to the action of a protein called Gephyrin. These findings shed light on key mechanisms of synaptic formation, which could allow researchers to further target synapse dysfunction and medical 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 machinery ready to sense GABA,” Chanda said.
“We used a gene-editing tool to remove the Gephyrin protein from neurons, which greatly reduced this autonomous assembly of synapses—confirming its important role regardless 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 convenient model, Chanda and his team were interested in testing the properties of the synapse in a human cellular environment that could ultimately be more easily translated into treatment.
To achieve this, his team cultured human stem cells to create brain cells that could mimic the properties of human neurons and synapses. They then performed large-scale, high-resolution imaging of these neurons and monitored their electrical activity 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. This makes understanding its basic cellular function an important first step toward treatment and prevention.
“Now that we have a better understanding of 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 to predict or intervene in this process,” he said.
About this genetics and neurology research
Author: Joshua Rhoten
Source: Colorado State University
Contact: Joshua Rhoten – Colorado State University
Picture: Image is credited to 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
Abstract
Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release
Synapses containing γ-aminobutyric acid (GABA) form the primary centers for inhibitory neurotransmission in our nervous system. It is unclear how these synaptic structures form and how they align their postsynaptic machinery with 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 is virtually devoid of any vesicular GABA release.
We found that several GABAAND receptor (GABAANDR) subunits, postsynaptic scaffolds, and major cell adhesion molecules can reliably coagulate and colocalize even in GABA-deficient subsynaptic domains, but remain physically separated from glutamatergic counterparts.
Genetic deletions of both gephyrin and the gephyrin guanosindi- or triphosphate (GDP/GTP) exchange factor, Collybistin, severely disrupted the assembly of these postsynaptic assemblies and their proper apposition with presynaptic inputs.
Gephyrin – GABAANDR clusters, developed in the absence of GABA transmission, could subsequently be activated and even potentiated by a delayed influx of vesicular GABA. Thus, the molecular organization of GABAergic postsynapses may initiate through an intrinsic GABA-independent but gephyrin-dependent mechanism.