The human brain forms synapses — microscopic connections between neurons in the brain — to record thoughts, memories and ideas. When 100-billion neurons need to find their connections, the biology behind the process is complex, to say the least.

Assistant Biochemistry Prof. Hisashi Umemori said many debilitating diseases, including autism, epilepsy and schizophrenia, could be linked to certain neurodevelopmental dysfunctions that occur when brain structures fail to properly mature.

Umemori’s research was published in the scientific journal, Nature, on Sept. 15.

At the molecular level, these dysfunctions are caused by improper wiring of synapses. Recently, Umemori’s lab identified an important new molecule, SIRP-alpha, which is involved in the process of synapse maturation in the brain, thus opening the door to possible therapeutic treatments.

“These diseases are caused by defects during synapse formation, so that’s why understanding the steps of these molecules — by which the brain is formed — we hope to contribute to the treatment and prevention of those diseases,” Umemori said.

The lab is exploring neuron connectivity and brain development, especially the pathways by which the brain systems become wired early in life.

“Neurons are precisely connected to each other, meaning each neuron knows exactly where to connect,” Umemori said. “We’re interested in how such a precise network is formed.”

Neuronal pathways in the brain are formed in two distinct steps, Umemori said. The first step, which begins at birth and continues until adolescence, establishes the initial connections between neurons and forms a preliminary network.

In the second step, the connections are either reinforced or eliminated based on the amount of activity they encounter, establishing a “functional circuitry,” Umemori said.

“In the beginning, we usually have excess synapses, so we choose good ones,” he said. “Active ones will be stabilized and inactive ones will be eliminated, so that we will basically have the most efficient circuitry in the brain.”

While the lab’s research involves development of the brain over time, the recent findings focus on the molecular mechanisms that underlie the process of synapse maturation in the second step of the process.

In particular, Umemori’s lab has confirmed the role a new molecule in this step: signal regulatory protein-alpha. SIRP-alpha travels between pre- and post-synaptic neurons, binding with specific receptors that tell the neuron to reinforce the synaptic connection.

“SIRP is basically used as a communication tool between pre- and post-synaptic cells to tell them that this is an active synapse,” Umemori said.

The molecule was discovered in 2010 in a research study focusing primarily on the first step of neuron development. It wasn’t until the lab’s most recent publication that they realized the importance of this molecule in synaptic reinforcement was realized.

In the search for molecules involved in the synapse maturation process, Umemori’s lab screened brain tissue samples in culture — placing neurons in contact with a variety of molecules thought to play a role in synapse development.

After identifying cultures with active synapse formation, the tissue samples underwent a procedure known as biochemical purification, which separates molecules based on different characteristics such as size or charge.

In future studies, Umemori said the lab hopes to analyze the effects of synapse dysfunction in schizophrenia using genetically modified mice, often called knockouts. While these mice are thought to express schizophrenia, the lab plans to run behavioral studies to confirm the presence of this trait — or “phenotype” — and its link to synaptic development.

“We have the knockout animals, and knockout animals do have synaptic changes, but we don’t know if they have different phenotype yet,” Umemori said. “If the animals show schizophrenic phenotype then we can try to treat (them) and see if that can be a disease model.”

Additionally, future research in the lab will examine other areas of the brain, since the recent findings were isolated to specific regions like the hippocampus.

Erin Johnson-Venkatesh, a postdoctoral research fellow in the lab, plans to expand the research to cover other aspects of synapse development.

“The paper focuses only on excitatory synapses,” Johnson-Venkatesh said. “Inhibitory synapses also may be affected, so I’m trying to figure out why and how.”

Although the research has potentially broad implications for clinical treatments of neurodevelopmental diseases, Johnson-Venkatesh said the molecular processes tend to dominate the day-to-day focus of the lab. Only when a project reaches the publication stage does she come to fully realize the impact of such work.

“You get really engrossed in a particular set of experience and sometimes you forget to even come up for air and all of a sudden … we need to write a paper and share these results,” she said. “Usually at the beginning and the end you sort of think more larger picture, and in the middle you’re just focused.”

Two University alumni, Anna Toth and Lily Zhang, both contributed to this recent publication. Given their success in this field, Johnson-Venkatesh offered advice to undergraduates interested in pursuing research.

“I think finding something you’re interested in is probably the most important,” she said. “And the second most important is finding an environment that you like working in … because then you’re going to enjoy being there.”

Alexandra Soos and Madison Dettlinger contributed reporting.

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