Synaptic specificity is collectively determined by partner identity, location and activity

Abstract

Our nervous system is organized into circuits with specifically matched and tuned cell-to-cell connections that are essential for proper function. The mechanisms by which presynaptic axon terminals and postsynaptic dendrites recognize each other and establish the correct number of connections are still incompletely understood. Sperry's chemoaffinity hypothesis proposes that pre- and postsynaptic partners express specific combinations of molecules that enable them to recognize each other. Alternatively, Peters' rule proposes that presynaptic axons and postsynaptic dendrites use non-partner-derived global positional cues to independently reach their target area, and once there they randomly connect with any available neuron. These connections can then be further refined by additional mechanisms based on synaptic activity. We used the tractable genetic model system, the Drosophila embryo and larva, to test these hypotheses and elucidate the roles of 1) global positional cues, 2) partner-derived cues and 3) synaptic activity in the establishment of selective connections in the developing nerve cord. We altered the position or activity of presynaptic partners and analyzed the effect of these manipulations on the number of synapses with specific postsynaptic partners, strength of functional connections, and behavior controlled by these neurons. For this purpose, we combined 2 developmental live imaging, electron microscopy reconstruction of circuits, functional imaging of neuronal activity, and behavioral experiments in wildtype and experimental animals. We found that postsynaptic dendrites are able to find, recognize, and connect to their presynaptic partners even when these have been shifted to ectopic locations through the overexpression of receptors for midline guidance cues. This suggests that neurons use partner-derived cues that allow them to identify and connect to each other. However, while partner-derived cues are sufficient for recognition between specific partners and establishment of connections;; without orderly positioning of axon terminals by positional cues and without synaptic activity during embryonic development, the numbers of functional connections are altered with significant consequences for behavior. Thus, multiple mechanisms including global positional cues, partner-derived cues, and synaptic activity contribute to proper circuit assembly in the developing Drosophila nerve cord.

Synaptic Specificity, Recognition Molecules, and Assembly of Neural Circuits

“…The importance of neural activity for late steps in neural development is clear. For example, absolute and relative activity levels regulate refinement and maintenance of synaptic patterns (Okawa et al, 2014;Valdes-Aleman et al, 2019). It is also clear that elaborate patterns of synaptic connectivity can form in the absence of neural activity (Harrison, 1904;Verhage et al, 2000).…”

Useful road maps: studying Drosophila larva’s central nervous system with the help of connectomics

“…The comparatively small size enables rapid reconstruction of connectomes from multiple individuals ( e.g. [ 76 ]) and opens doors to an exciting new area of experimental connectomics to address questions about the structural correlates of specific memory traces, individual differences in circuits that underlie distinct personality traces, and discovering the effects of various mutants on the circuit architecture.…”

Connectomes across development reveal principles of brain maturation

“…Serial-section electron microscopy (EM) allows reconstruction of neural circuits with synapse resolution [14][15][16][17][18][19][20] , but low throughput makes it difficult to compare whole brain samples and comprehensively assess plasticity. EM has been applied to assess wiring differences between species 21 , sexes 22 , genotypes 23 , and ages 4,24 . But previous studies mapped partial circuits or few samples.…”