Adolescence is a pivotal period not only for social and physical change, but also for brain development. During these years, higher mental functions such as planning, reasoning, and decision-making continue to mature. Even so, researchers do not yet fully understand how the brain’s complex networks are refined during this critical window.
Synapses—the functional connections that enable neurons to communicate—are central to this process. For decades, a dominant view has been that synapse numbers rise through childhood and then drop in adolescence. This idea helped fuel the “synaptic pruning” hypothesis: that removing weak or unused connections plays a major role in adolescent brain development and that excessive pruning could contribute to neuropsychiatric disorders. Schizophrenia, which can involve hallucinations, delusions, and disorganized thinking, has often been discussed in this context.
New Findings Challenge the Classic Pruning Narrative
Researchers at Kyushu University now report evidence that complicates this long-standing model. In a study published in Science Advances on January 14, the team found that the adolescent brain may not only eliminate connections, but also build new ones—forming tightly packed clusters of synapses in specific parts of neurons during adolescence.
Professor Takeshi Imai of Kyushu University’s Faculty of Medical Sciences said the work was not originally aimed at brain disorders. After developing a high-resolution method for synapse analysis in 2016, the team began examining the mouse cerebral cortex and noticed an unexpected pattern: a previously unrecognized, high-density “hotspot” of dendritic spines—tiny protrusions on dendrites where excitatory synapses typically form.
Focusing on a Crucial Layer of the Cerebral Cortex
The cerebral cortex is organized into six layers that work together to create complex neural circuits. The researchers focused on neurons in Layer 5, which integrate information from multiple sources and send output signals to other brain regions. Because of this role, Layer 5 neurons are often considered a key control point in cortical information processing.
To examine these neurons in detail, the team combined a tissue-clearing technique called SeeDB2 (developed by Imai’s group) with super-resolution microscopy. This approach made it possible to analyze cleared, transparent brain tissue and map dendritic spines across entire Layer 5 neurons at a level of detail that had not been achieved previously.
A Synapse “Hotspot” That Appears During Adolescence
The mapping revealed a striking pattern: one particular segment of the dendrite contained an unusually dense concentration of dendritic spines, forming what the researchers describe as a synaptic “hotspot.” Importantly, this hotspot did not appear early in life—it emerged during adolescence.
By tracking spine distribution across development, the team found that in two-week-old mice (before weaning), spines were relatively evenly distributed across the neuron. Between three and eight weeks of age—a period spanning early development into adolescence—spine density rose sharply in a single region of the apical dendrite. Over time, this localized growth led to a dense cluster consistent with a newly formed synaptic hotspot.
Imai said the results suggest that the widely cited “adolescent synaptic pruning” hypothesis may need to be revisited, as pruning may not be the only major synaptic process during this stage.
What Researchers Want to Learn Next
The discovery could also influence how scientists think about the origins of certain brain disorders. Ryo Egashira, the study’s first author, said that while pruning may occur broadly, the formation of new synapses may happen in specific dendritic compartments during adolescent cortical development. Disruption of this localized synapse-building process, he suggested, could be an important factor in at least some forms of schizophrenia.
To explore that possibility, the researchers studied mice carrying mutations in genes linked to schizophrenia, including Setd1a, Hivep2, and Grin1. Early development appeared largely typical, with normal spine density up to around two to three weeks after birth. During adolescence, however, synapse formation was substantially reduced, and the hotspot failed to develop properly.
Schizophrenia has long been framed primarily as a disorder driven by excessive synapse loss. These findings point to another possibility: that impaired synapse formation during adolescence may play a significant role. The researchers cautioned, however, that the study was conducted in mice, and it remains unclear whether the same mechanism occurs in primates or humans.
What researchers want to learn next
Looking ahead, Imai said the team hopes to identify which brain regions are connecting through these newly formed synapses during adolescence. Pinpointing the circuits involved could clarify what is being built during this developmental period and help researchers better understand both typical brain maturation and the biological pathways that may contribute to neuropsychiatric disorders.
