Specific sets of intrinsic and extrinsic factors drive excitatory and inhibitory circuit formation.

How are excitatory (glutamatergic) and inhibitory (GABAergic) synapses established? Do distinct molecular mechanisms direct differentiation of glutamatergic and GABAergic synapses? In the brain, glutamatergic and GABAergic synaptic connections are formed with specific patterns. To establish such precise synaptic patterns, neurons pass through multiple checkpoints during development, such as cell fate determination, cell migration and localization, axonal guidance and target recognition, and synapse formation. Each stage offers key molecules for neurons/synapses to obtain glutamatergic or GABAergic specificity. Some mechanisms are based on intrinsic systems to induce gene expression, whereas others are based on extrinsic systems mediated by cell-cell or axon-target interactions. Recent studies indicate that specific formation of glutamatergic and GABAergic synapses is controlled by the expression or activation of different sets of molecules during development. In this review, the authors outline stages critical to the determination of glutamatergic or GABAergic specificity and describe molecules that act as determinants of specificities in each stage, with a particular focus on the synapse formation stage. They also discuss possible mechanisms underlying glutamatergic and GABAergic synapse formation via synapse-type specific synaptic organizers.