Synaptogenesis as a Coordination Game: A Game-Theoretic Framework for Understanding Synapse Formation

Synapse formation requires precise coordination between pre- and postsynaptic neurons, yet theoretical frameworks for understanding this bilateral process remain underdeveloped. This paper proposes that synaptogenesis can be formally modeled as a coordination game from game theory. In this framework, pre- and postsynaptic neurons are players whose strategies consist of molecular expression profiles (neurotransmitters, receptors, scaffolding proteins). Stable synapses correspond to Nash equilibria—configurations where neither neuron benefits from unilaterally changing its molecular strategy. Trans-synaptic adhesion molecules (neurexin-neuroligin) function as coordination devices that facilitate equilibrium selection rather than serving as structural synapse components. Empirical validation using the complete C. elegans connectome (279 neurons, 2,194 synapses) and neuron-level gene expression data (955 genes) reveals: • 7.5-fold excess reciprocity compared to random networks (p < 10⁻⁶⁵) • Non-random neurotransmitter-type coordination (χ² = 245, p < 10⁻³³) • Connected pairs show 2.1× higher gene expression similarity (p < 10⁻²⁹) • Glutamate receptors show 4-6× enrichment in connected pairs • Both "matching" and "complementary" coordination patterns observed The framework explains why neurexin-neuroligin knockouts shift synapse-type ratios rather than eliminating synapses, provides a principled account of activity-dependent refinement as iterated game play, and suggests that developmental disorders may involve convergence on suboptimal equilibria. Data sources: Cook et al. (2019) Nature; Arnatkeviciute et al. (2018) PLoS Comp Biol; WormBase WS256.