Insights into brain architecture

Interactions between cells in the cerebellum—or ‘little brain’—are essential for normal function. A collaboration of Japanese researchers has now found that the proper development of the tree-like morphology of Purkinje cells in the cerebellum requires signals from other cerebellar cells called granule cells.

The cerebellum is a region of the brain (Fig. 1) that coordinates sensory information. Lesions in the cerebellum cause subtle defects in movement and balance, and some evidence suggests conditions such as schizophrenia are caused by cerebellar dysfunction.

Unique to the cerebellum are the specialized Purkinje cells (Fig. 2)—named for the Czech anatomist Jan Purkynĕ. Development of the great numbers of Purkinje cell ‘branches’ or dendrites, which project into the outer layer of the cerebellum where they interact with other neurons such as parallel fibers, is essential for cerebellar function.

Remarkably, although the cerebellum represents only about 10% of total brain size, the number of cerebellar neurons constitutes some 50% of total brain neurons. Upwards of 60 billion granule cells occupy the inner region of the cerebellum.

The collaboration of neuroscientists led by Katsuhiko Mikoshiba and Chihiro Hisatsune of the RIKEN Brain Science Institute, Wako, found that signals produced by granule cells are required for proper growth of the complex Purkinje cells¹. The team evaluated mice that lack inositol 1,4,5-triphosophate receptor type 1 (IP₃R1), a signaling protein found throughout the brain.

By studying isolated Purkinje cells and granule cells from normal mice and mice lacking IP₃R1, the team showed that granules cells, not Purkinje cells, need IP₃R1 in order to produce brain-derived neurotrophic factor (BDNF), a growth factor that Purkinje cells need for development of their tree-like dendrites.

The team also visualized dendrite branches of Purkinje cells in brains of mice that lack IP₃R1. Compared to normal mice, the IP₃R1-deficient brains showed reduced connections between Purkinje cells and parallel fibers in the outer layer of the cerebellum, clearly implicating IP₃R1 in regulating normal cerebellar development.

“We now want to know the molecular mechanism by which IP₃R1 regulates BDNF expression from granule cells,” says Mikoshiba. “And because IP₃R1 is found in many regions of the brain, future work will hopefully reveal the physiological roles of IP₃R1 in cells forming these other regions as well.”

Understanding the architecture of the brain requires understanding how individual neurons interact with one another. Mikoshiba and colleagues’ work highlights the complex interactions between cerebellar Purkinje cells and granule cells that are required for forming correct connections between them.