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Coupling migration and axon targeting optimisation

21/06/18

Researchers in Oscar Marin’s lab at King’s College London’s CND, in collaboration with the University of Edinburgh, have identified a key developmental program that dictates brain circuit formation.

For many years, scientists have assumed that developing brains are wired through an orderly sequence of developmental steps, starting from the birth of neurons, migration to the appropriate place in the brain, and finally formation of appropriate connections with other neurons. This commonly accepted view makes each event independent of each other. Improper brain circuit connections seen in some neuropsychiatric diseases, such as autism, are commonly interpreted as defects in synapse formation rather than as a consequence of events that precede this final step in brain wiring.

The study published by Lynette Lim and colleagues in the July issue of Nature Neuroscience challenges this viewpoint and brings novel insights to our understanding of how connections are formed during the development of the cerebral cortex. In the cortex, two major classes of neurons exist – the workhorse neurons are excitatory cells while inhibitory interneurons control and fine tune local function. During developmental stages, these two major classes of neurons must migrate from different places to their final destination in the cortex and form synaptic connections with each other.

Lim and colleagues found that brain circuit wiring is determined much earlier than initially anticipated. The authors used cortical inhibitory interneurons as a model to study how each developmental program could ultimately affect circuit formation. It has long been known that these inhibitory neurons are born outside the cortex, and during embryonic stages, they migrate long distances to get to their destination. Curiously, inhibitory neurons follow multiple migratory routes, distinct from the ones used by excitatory cells. Why they migrate along different routes has been, however, unclear.

Since interneurons are highly diverse population, Lim and colleagues hypothesise that cell identity might dictate route choices. Distinct subtypes of interneuron are classified by their connecting partners, axonal, and morphological characteristics. The researchers exploited this model and found that depending on the connecting partners and characteristic subtype of interneuron, these cells display a strong bias for a particular migratory route on their way to the cerebral cortex. The authors went on to show that route choice is a behaviour that is mechanistically linked to the normal targeting of their characteristic axonal arbours. Decoupling the processes of migration and synapse formation leads to abnormal axonal targeting and impairs information processing in the cerebral cortex of adult mice. In other words, migration and synapse formation are intimately related to each other, at least for some classes of neurons.

In summary, these experiments demonstrate that neuronal migration is directly linked to axon targeting. These results reshape the way we understand brain development and point to a high degree of coordination between different developmental programs during the assembly of neural circuits. As the first author, Dr Lynette Lim points out, “In many brain disorders such as autism or schizophrenia in which there are clear defects in brain wring, researchers often focus on what goes wrong in synapse formation. Our work points to the need to examine disease aetiologies in a holistic manner because developmental events are interrelated complex phenomena that contribute to proper brain function.”