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Proteomic Study Points to Stretched-Out Synapse Development in Humans

NEW YORK – New proteomic research suggests human brain development involves an extended period of synapse formation compared to that found in other mammals, meaning there may be longer stretches of time where alterations in these connections between nerve cells in the brain can occur. The findings appeared in the journal Nature on Monday.

"Overall, this study provides valuable insights into how human synapses develop differently from those in other species, shedding light on the molecular mechanisms behind brain development, cognitive abilities, and the risk of brain disorders," senior author Arnold Kriegstein, a neurology researcher at UCSF, and first author Li Wang, a regeneration medicine, stem cell, and neurology researcher at UCSF, said in an email. "It is an essential step towards understanding [human intelligence] and how it sets us apart from other animals."

To get a detailed look at the dramatic synapse changes that are believed to occur during the development process, the researchers performed proteomics-based analyses at different stages across synapse development in the neocortex of humans and other mammalian species, including the mouse and rhesus macaque.

Using a combination of liquid chromatography, tandem mass spectrometry, and label-free protein quantification, the team tracked more than 1,000 proteins in samples collected between around 18 to 23 weeks gestation and adulthood, focusing on "postsynaptic density" proteins.

When they used postsynaptic density protein patterns to untangle synapse development in humans, mice, and macaques, for example, the investigators found that the process took roughly two to three times longer in humans than it did in the other mammalian species considered — results backed up by their subsequent single-cell RNA sequencing analyses on neocortex cells from the adult human neocortex.

"This difference is especially noticeable in the part of the brain responsible for our thoughts and emotions," Kriegstein and Wang explained, adding that human synapses "have more of certain proteins called Rho guanine nucleotide exchange factors (RhoGEFs), especially around the time we are born."

Based on their findings so far, the researchers suggested the leisurely maturation rate found in human synapses may be a consequence of this elevated RhoGEF representation. In the past, they explained, RhoGEFs and proteins associated with them have been implicated in processes such as intelligence, synaptic plasticity, developmental delays, and intellectual disability.

"These results link the slow development of human synapses to the evolution of human cognition," Kriegstein and Wang noted. "The more extended plasticity period in humans, particularly during infancy and early childhood, may increase our ability to change and adapt in response to experiences, learning, and environmental stimuli."

On the other hand, the authors noted that the extended development stage described in the study may leave the brain open to environmental or genetic processes that can alter development over a greater period of time, perhaps contributing to some neurodevelopmental conditions or psychiatric diseases.

"The main finding is that human synapses remain immature and plastic (malleable) for a prolonged period in the first few years of life," Kriegstein and Wang said, noting that "findings from this study have the potential to pinpoint the critical stages of susceptibility in various brain disorders and pave the way for the creation of precisely tailored therapeutic interventions."