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Cortical wiring by synapse type-specific control of local protein synthesis


The cerebral cortex is responsible for our most sophisticated and diverse behaviours, including those that define us as humans. It is also one of the most complex biological systems, so understanding the mechanisms that control its development is a major scientific challenge. There are two main types of neurons in the cerebral cortex, excitatory pyramidal cells and inhibitory interneurons. The interaction between excitatory and inhibitory neurons is crucial for the normal function of the cerebral cortex. Inhibitory interneurons pace and synchronise the activity of excitatory neurons, thereby orchestrating behaviour.

Neurons in the cerebral cortex organise in networks wired by individual connections known as synapses. Like an electrical connection, synapses consist of pre- (power plug) and post-synaptic (socket) compartments. The local control of protein synthesis is critical for the function of the cerebral cortex because it endows neurons with a mechanism through which they can influence the activity of individual synapses. Local protein synthesis occurs in both pre- and post-synaptic compartments in the adult brain. However, it is unknown to what extent local translation is differentially regulated at the level of specific synaptic connections and whether this mechanism is used during brain development.

In new research published in Science, a collaborative study from the Rico and Marín laboratories led by Clémence Bernard reports that the local control of protein synthesis occurs in a cell-type and even synapse-type specific manner to establish cortical connectivity during brain development. The authors identified a signalling pathway that controls local translation in one of the most fundamental connectivity motifs in the cerebral cortex, the synapses made by excitatory pyramidal cells on parvalbumin-positive interneurons.

Abnormal synthesis of synaptic proteins is a core pathophysiological mechanism in autism spectrum disorder (ASD). The molecular programme identified by Bernard and colleagues involves several proteins encoded by genes associated with neurodevelopmental disorders, supporting the idea that the synapses made by excitatory pyramidal cells on parvalbumin-positive interneurons might be particularly sensitive to alterations in developmental brain conditions such as ASD.