Synaptic engineering: An ionic switch of behavior

Abstract

The unraveling of the human brain connectivity map is considered by many as an essential step in the understanding how the brain controls behavior and how brain malfunction underlies behavioral disorders. Although the behavioral output of neural networks depends on a delicate balance between excitatory and inhibitory synaptic connections, the neural connectivity map does not carry information about the sign of synaptic connections.. Is it possible to reverse the behavioral output of a neural circuit by changing the sign of a synapse? Does the sign of a synapse provide constraints to the development, the specification, and behavioral output of a connectome? Here, we address these questions using the neuronal circuit that mediates the C. elegans escape response. In the escape response a single pair of tyraminergic neurons coordinate the suppression of head movements with backward locomotion through the activation of an inhibitory postsynaptic receptor, the tryamine-gated chloride channel LGC-55. LGC-55 is a member of the Cys-loop ligand gated ion channel (LGIC) family, whose ion selectivity is determined by the M2 domain. Amino acid substitution of the M2 domain LGC-55 allowed us to change the selectivity from Clto Na+ and K+ . We generated transgenic animals that express the excitatory LGC-55 cation channel under control of its endogenous promoter in an LGC-55 anion mutant background. A fluorescently tagged LGC-55 cation channel localizes opposite to tyramine release sites indistinguishable from the wild-type LGC-55 anion channel. Exogenous tyramine induces neck muscle relaxation and backward locomotion in the wild-type LGC-55 anion animals, but induces neck muscle contraction and forward locomotion in transgenic animals that express the LGC-55 cation. Similarly, touch or optogentically induced release of endogenous tyramine triggers opposite behavioral responses in animals that express the LGC-55 cation vs LGC-55 anion channel. Our data show that changing the nature of a synapse within a neural circuit can reverse its behavioral output and indicate that the C. elegans connectome is established independent of the nature of synaptic activity or behavioral output.