New Model Unveils Synaptic Mechanisms in Neurological Diseases

Newly released research from Colorado State University provides basic answers to questions regarding brain cellular connectivity that may be helpful in the development of therapies for neurological conditions like schizophrenia, epilepsy, and autism.

The study, published in the Proceedings of the National Academy of Sciences, focuses on how highly specialized subcellular structures called synapses allow brain neurons to communicate with one another.

Pathogenic mutations in the genes that affect these delicate structures’ development can result in severe mental disorders. These structures are essential for electrochemically signaling the control of numerous processes throughout the nervous system. Assistant Professor Soham Chanda stated that little is known about how synapses form and function, despite their critical role in connecting neurons in various brain regions.

Chanda and colleagues at the Department of Biochemistry and Molecular Biology concentrated on a particular and significant kind of synapse known as GABAergic to provide an answer to that central query. According to Chanda, scientists studying neuroscience have long postulated that the formation of these synapses may result from a neuron's release of GABA molecules and the nearby neuron's corresponding sensing activity.

Studies presented in this paper now demonstrate that these synapses can start to form independently of neuronal communication, primarily as a result of the scaffolding function of a protein known as gephyrin. With a clearer understanding of the fundamental processes underlying synaptic formation, researchers may be able to concentrate more on synapse dysfunction and potential medical interventions.

Chanda’s group created a brain model from human neurons created from stem cells that allowed them to thoroughly test these connections. Using a gene-editing tool known as CRISPR-Cas9, the group was able to genetically modify the system and validate the function of Gephyrin in synapse formation.

Our study shows that even if a pre-synaptic neuron is not releasing GABA, the post-synaptic neuron can still put together the necessary molecular machineries prepared to sense GABA. We used a gene-editing tool to remove the Gephyrin protein from neurons, which largely reduced this autonomous assembly of synapses – confirming its important role irrespective of neuronal communication.”

Soham Chanda, Assistant Professor, Colorado State University

Using Stem Cells to Advance Understanding of Neuron and Synapse Formation

Historically, neuroscientists have employed rodent models to examine these brain synaptic connections. That offers a good model, but Chanda and colleagues wanted to test synapse properties in a human cellular setting so that the results could be more easily applied to therapeutics in the future.

Chanda group developed human stem cells to create brain cells that could imitate human synapses and neurons to accomplish this. To comprehend synaptic mechanisms, the group subsequently tracked the electrical activity of these neurons through extensive high-resolution imaging.

Chanda said that several mutations in the Gephyrin protein have been associated with neurological disorders like epilepsy, which alters neuronal excitability in the human brain. That 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 the ways one can predict or intervene in that process.”

Soham Chanda, Assistant Professor, Colorado State University