Rutgers University-Newark scientists seek to chart a chain reaction that starts with a mutation.
The development of the human brain, which begins in the womb and continues long after birth, is an elaborate construction job. Guided by a person’s genes, and the proteins whose production they spawn, tens of billions of neurons (nerve cells) somehow find a way to come together one by one until the structure of the brain is complete. Yet the blueprints are not always followed and scientists are convinced that this produces variations in human behavior, one of which is autism.
“The brain, how it works, is based on one neuron connecting to another and then another, and forming these circuits,” explains Tracy Tran, an assistant professor in the Department of Biological Sciences at Rutgers University-Newark (RU-N). “That’s how the gross function of complex behavior develops.” The circuits form, she says, when each neuron extends a process, called an axon, secreting neurochemicals (neurotransmitters) used to communicate, via electrical impulses (synapses) with another neuron, usually on the dendrites. In the most simplistic example, the axon of neuron A would communicate with the dendrites on neuron B, and the axon from neuron B will pass along the processed information to the dendrites of neuron C, and so on until the loop of information comes back to first neuron – a simple circuit.
Tran leads a team that is looking into what makes the circuits form as they do, and potential ways to – in effect – rewire those connections to make them more conducive to healthy brain function during disease. The fundamental concept is that if we know how something is put together, then hopefully, we would be more equipped to fixing it when its broken or in the case for the brain when it is not functioning properly. As Tran describes it, what the team wants to know is, “how does any one particular neuron know to connect with neuron B and not neuron C or D or E? It must precisely connect with its proper target,” she explains, “because if it doesn’t that’s what results in many of the neurological diseases that we see such as autism.”
Scientific evidence suggests that a large family of proteins called semaphorins influences which neurons connect with each other during neural development. The proteins also appear to regulate the growth and physical structures of dendritic spines, which protrude, as tiny extensions, from the dendrites like thorns on a rosebush. Dendritic spines are sites for stimulatory (or excitatory) synapses, therefore, the more spines a neuron has – increasing the stimulation it can receive from other nerve cells, the more overloaded a neuron might become. It is a bit like having 20 spotlights shining into a person’s eyes where having just two lights would be much better. “If you don’t have the light you don’t see at all,” Tran explains, “but if you have too much of it, that’s not good.” Tran believes autism symptoms can arise when certain neurons are imbalanced with the number of stimulations they receive.
Along with RU-N colleagues James M. Tepper, a distinguished professor in the Center for Molecular and Behavioral Neuroscience; and Michael Shiflett, a research assistant professor of psychology with expertise in animal behavior, Tran wants to learn from start to finish how semaphorins affect these brain development processes. It is knowledge they then hope to apply to human autism.
Tran assembled this team with one of six Initiative for Multidisciplinary Research Team (IMRT) awards that RU-N granted to members of its faculty in 2015. The awards are funding varied research projects in both the physical and social sciences.
With her team’s $80,000 award, Tran will breed laboratory mice with a gene mutation that stops the production of semaphorins, causing the mutant mice to produce extra-spiny dendrites in their brains as is observed in humans with autism. Then – using equipment in his lab that measures brain activity in exquisite detail – Tepper will examine both the brains of those mice and brains of genetically normal mice, neuron by neuron, and record how differently nerve signals move through them. Shiflett will then compare the behaviors of the two sets of mice, with tests designed to detect any autistic tendencies.
Of course, many aspects of human autism are too sophisticated to appear in a creature such as a mouse. At the same time, says Shiflett, “you also can measure all sorts of behaviors in mice, from very simple behaviors like locomotion and processing of touch and sound, to fairly complex kinds of behaviors like decision-making and complex-attention kinds of tests. A lot of these tests are based on understanding the human condition.”
Shiflett will document how energetically mice with the gene mutations examine colorful new objects added to their environments, compared with how they treat similarly attractive objects they have seen before – a potential proxy for ways that humans with autism react to various people. Similarly, Shiflett will evaluate repetitive motions of the experimental mice, which also have an analog in people with autism.
The work by the RU-N team is extremely preliminary, and the gene connected with semaphorin is just one of hundreds that science has linked with autism. Tran knows she is addressing just a small slice of the spectrum. Still, it is conceivable that one day, gene therapy could help regulate brain formation before birth. Or, researchers might build on data from Tran’s lab suggesting that, at least in a culture dish, when semaphorin is added to neurons, “within hours we see a dramatic decrease in the number of spines.” Says Tran, “this gives a clue that these molecules can actively restrain the number of spines being formed in a very short time.” If hopes are realized, the finding could translate one day into effective treatments of the living human brain.
Shiflett says the IMRT award has been essential to moving the work forward, because none of the scientists on the team could have executed such a project in isolation. “There are so many benefits to collaborating,” he notes. “You can do so many more things.”
“We hope that we will find some really interesting results, and continue on,” adds Tran. “That’s the thing about science. After you find the answer to one question, that opens the door for many, many other questions. That’s part of the excitement.”
Photo of Tracy Tran (left) and Michael Shiflett by Nora Luongo