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 autonomous synapse development. This discovery increases the understanding of synaptic mechanisms and possible therapeutic approaches.
Key facts:
- The role of Gefirina: Essential for autonomous synapse formation in the brain.
- Research Method: Using CRISPR-Cas9 in human neurons derived from stem cells.
- Therapeutic potential: Insights 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 may 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 between 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 impair their development can cause severe mental disorders.
Despite their important role in connecting neurons in different brain regions, how synapses form and function is still not well understood, Assistant Professor Soham Chanda said.
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 neuroscientists have long hypothesized that these synapses may form due to a release of GABA and related sensory activity between two neurons in close proximity.
However, research in the paper now shows that these synapses can begin to develop autonomously and independently of that neuronal communication, largely 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 a pre-synaptic neuron is not releasing GABA, the post-synaptic neuron can still assemble the necessary molecular machinery primed 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 independent 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 this provides a convenient model, Chanda and his team were interested in testing properties of synapses in a human cellular environment that could ultimately be more easily translated into treatments.
To achieve this, his team cultivated human stem cells to form brain cells that can mimic the properties of human neurons and synapses. They then performed extensive high-resolution imaging of these neurons and tracked their electrical activities to understand synaptic mechanisms.
Chanda said that some mutations in the Gephyrin protein have been associated with neurological disorders such as epilepsy, which alters the excitability of neurons in the human brain. This makes understanding its basic 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 identify ways to predict or intervene in that process. he said.
About this news about genetic and neurological research
Author: Joshua Rhoten
Source: Colorado State University
Contact: Joshua Rhoten – Colorado State University
Image: Image is credited to Neuroscience News
Original research: Closed access.
“Gephyrin promotes autonomous assembly and synaptic localization of postsynaptic GABAergic components without presynaptic GABA release” by Soham Chanda et al. PNAS
ABSTRACT
Gephyrin promotes autonomous assembly and synaptic localization of postsynaptic GABAergic components without presynaptic GABA release
Synapses containing γ-aminobutyric acid (GABA) constitute the main centers for inhibitory neurotransmission in our nervous system. It is unclear how these synaptic structures form and connect 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 virtually lack any vesicular GABA release.
We found that some GABAor receptor (GABAorR) subunits, postsynaptic scaffolds, and key cell adhesion molecules can reliably assemble and colocalize even in GABA-deficient subsynaptic domains, but remain physically separated from glutamatergic counterparts.
Genetic deletions of the Gephyrin exchange factor and the Gephyrin-related guanosine di- or triphosphate (GDP/GTP) exchange factor, Collybistin, severely disrupted the assembly of these postsynaptic compounds and their proper placement with presynaptic inputs.
Gephyrin–GABAorR groups, developed in the absence of GABA transmission, can then be activated and even potentiated by the delayed supply of vesicular GABA. Thus, the molecular organization of GABAergic postsynapses may be initiated via an intrinsic GABA-independent but Gephyrin-dependent mechanism.