Synaptic combinatorial molecular mechanisms generate repertoires of innate and learned behavior

Abstract

Although molecular mechanisms underpinning specific behaviors have been described, whether there are mechanisms that orchestrate a behavioral repertoire is unknown. To test if the postsynaptic proteome of excitatory synapses could impart such a mechanism we conducted the largest genetic study of mammalian synapses yet undertaken. A repertoire of sixteen innate and learned behaviors was assessed from 290,850 measures in 55 lines of mutant mice carrying targeted mutations in the principal classes of postsynaptic proteins. Each innate and learned behavior used a different combination of proteins. These combinations were comprised of proteins that amplified or attenuated the magnitude of each behavioral response. All behaviors required proteins found in PSD95 supercomplexes. We show the vertebrate increase in proteome complexity drove an expansion in behavioral repertoires and generated susceptibility to a wide range of diseases. Our results reveal a molecular mechanism that generates a versatile and complex behavioral repertoire that is central to human behavioral disorders.

A combinatorial postsynaptic molecular mechanism converts patterns of nerve impulses into the behavioral repertoire

“…There are three features in common between the results obtained from the genetic dissection of electrophysiological functions described above and the behavioral data presented in the companion manuscript 35 . First, combinations of postsynaptic proteins specify each innate or learned behavioral response, and each synaptic response to temporally encoded information.…”

“…Here, we report a large-scale genetic dissection of the role of postsynaptic proteins in multiple forms of synaptic plasticity induced by elementary patterns of activity. In addition to a side-by-side comparative study of the electrophysiological phenotypes of mutations in many genes, we have measured innate and learned behavioral responses and hippocampal transcriptomes in the same mutant mouse lines 35 . These studies comprise the largest genetic analysis of the vertebrate synapse to date with phenotyping in molecular, electrophysiological and behavioral domains obtained using standardized quantitative approaches and analyzed with robust statistical methods.…”

Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning

“…Our data adds to the recent and rapidly expanding use of model organism phenomics to discover the functions of poorly characterized genes identified through genomic sequencing. 44,101,[153][154][155][156][157][158] We have shown how such data can be used to identify novel genetic interactions, establish variant functional assays, and develop tests of phenotypic reversibility.…”

A lifespan program of mouse synaptome architecture

“…In recent years it has become firmly established that the proteome composition of synapses controls the physiological mechanisms of behavior. The postsynaptic proteome of excitatory synapses (the main class of brain synapse) is highly complex (9)(10)(11)(12)(13) and genetic studies have shown that the individual proteins regulate many innate and learned behaviors in the behavioral repertoire (14)(15)(16)(17). Moreover, mutations in these proteins cause over 130 brain diseases (10), including common disorders that characteristically arise in childhood, adolescence, young or elderly adults.…”

“…Synapses were labelled using fluorescent tags on the endogenous PSD95 (PSD95-eGFP) and SAP102 (SAP102-mKO2) proteins (18). These two postsynaptic scaffold proteins assemble signaling complexes containing neurotransmitter receptors, structural proteins and signaling enzymes (13,20,21) that play a key role in synaptic plasticity and innate and learned behaviors (15,16,(22)(23)(24).…”