Kyushu University analyzes mouse cerebral cortex and finds synapses increase during adolescence: Promoting development of higher brain functions

In the cerebral cortex, synapses increase during the early postnatal juvenile period, then are pruned during adolescence, reducing the number of synapses. The prevailing theory holds that excessive synaptic pruning leads to schizophrenia, while insufficient pruning leads to autism spectrum disorder. Overturning this established theory, researchers have discovered that during adolescence, spines are formed in large quantities in specific parts of layer 5 pyramidal cells in the cerebral cortex. This was revealed by a research group that included Professor Takeshi Imai and Graduate Student Ryo Egashira (at the time of the research) from the Faculty of Medical Sciences, Kyushu University, Researcher Meng-Tsen Ke from RIKEN (at the time of the research), Assistant Professor Nao Nakagawa-Tamagawa from the Graduate School of Medical and Dental Sciences, Kagoshima University, and Professor Tsuyoshi Miyakawa from Fujita Health University. Their findings were published in Science Advances.

Because the synaptic pruning theory was proposed based on the average density of synapses, very little research has been conducted on how dendritic spines are distributed in each of the diverse types of neurons in the cerebral cortex and how they change during the developmental process. This is because dendritic spines are extremely small, making them difficult to observe.

In previous research, Imai and his colleagues developed a clearing reagent called SeeDB2 for three-dimensional observation of neuronal morphology in the brain. This time, by combining it with super-resolution microscopy, they were able to accurately capture dendritic spines that are less than one micron in size.

In this study, the researchers focused on layer 5 pyramidal cells, which are key to information processing in the mouse cerebral cortex, and comprehensively analyzed the distribution of dendritic spines where excitatory synapses exist. As a result, they found that in the apical dendrites extending from layer 5 to layer 1, spines are rarely seen at the tip or base but are accumulated at high density toward the middle.

Furthermore, when they investigated how the high-density accumulation of dendritic spines is formed during the developmental process, they found that in all dendritic regions, spines increased dramatically from one week to two weeks of age (corresponding to the infant period). Subsequently, until eight weeks of age (adolescence), spine density gradually decreased in many regions, including basal dendrites. On the other hand, in the middle part of the apical dendrites, spine density continued to increase even during adolescence, ultimately forming high-density accumulation sites.

Higher brain functions such as complex thinking and prediction are thought to develop during adolescence. Additionally, it is known that several psychiatric disorders, including schizophrenia, first manifest around adolescence, suggesting that abnormalities in adolescence-specific circuit development mechanisms may be involved in these disorders.

When the researchers removed the whiskers of mice immediately after birth and raised them without tactile stimulation from whiskers, they found that high-density accumulation sites of dendritic spines were not formed in layer 5 pyramidal cells of the somatosensory cortex responsible for whisker sensation. On the other hand, dendritic spine density was normal in other dendrites. This suggests that adolescent dendritic spine formation in high-density accumulation sites occurs in an experience-dependent manner.

When the Setd1a gene, known to be associated with the development of schizophrenia in humans, was knocked out in layer 5 pyramidal cells and spine density was analyzed, the spine density in both basal and apical dendrites of three-week-old mice was unchanged from the control group, whereas in adult mice, spine density was reduced in the middle part of apical dendrites. This is thought to be because the Setd1a gene mutation impaired adolescence-specific spine formation. Similar results were obtained with mutations in other schizophrenia and intellectual disability-related genes such as Grin1 and Hivep2.

Imai commented: "At least some cases of schizophrenia may be linked to abnormalities in the spine formation process that cause symptoms. In the future, we would like to examine the synaptic formation process throughout the entire brain to clarify the complete picture of brain development during adolescence. Also, since some antidepressants have the effect of increasing spines, I hope this will lead to the development of treatments in the future."

Journal Information
Publication: Science Advances
Title: Dendritic compartment-specific spine formation in layer 5 neurons underlies cortical circuit maturation during adolescence
DOI: 10.1126/sciadv.adw8458