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

Abstract

How is the information encoded within patterns of nerve impulses converted into diverse behavioral responses? To address this question, we conducted the largest genetic study to date of the electrophysiological and behavioral properties of synapses.Postsynaptic responses to elementary patterns of activity in the hippocampal CA1 region were measured in 58 lines of mice carrying mutations in the principal classes of excitatory postsynaptic proteins. A combinatorial molecular mechanism was identified in which distinct subsets of proteins amplified or attenuated responses across timescales from milliseconds to an hour. The same mechanism controlled the diversity and magnitude of innate and learned behavioral responses. PSD95 supercomplex proteins were central components of this synaptic machinery. The capacity of vertebrate synapses to compute activity patterns increased with genome evolution and is impaired by disease-relevant mutations. We propose that this species-conserved molecular mechanism converts the temporally encoded information in nerve impulses into the repertoire of innate and learned behavior.

Synaptic combinatorial molecular mechanisms generate repertoires of innate and learned behavior

“…In a companion manuscript we study the electrophysiological properties of synapses in the CA1 region of the hippocampus in the same set of mutant mice. This shows that the combinatorial mechanism defined here is important in computing the information encoded in patterns of neuronal activity and in controlling both short-and long-term plasticity 28 . We go on to integrate the behavioral and electrophysiological datasets to show that this species-conserved molecular mechanism converts the temporally encoded information in nerve impulses into the repertoire of innate and learned behavior.…”

“…The most severe behavioral perturbations were caused by proteins encoding components of PSD95 supercomplexes. These high molecular weight multiprotein complexes encompass neurotransmitter receptors, ion channels and signaling proteins 13,[19][20][21]44,45 that control short-and long-term synaptic plasticity 28,42,46,47 . Important components of these supercomplexes include the NMDA receptor and proteins interacting with AMPA receptors 13,19,21 .…”

“…We also measured several forms of learning and memory in order to assess whether their genetic mechanisms were distinct from those regulating innate behaviors. In addition to designing a large-scale behavioral experiment, we also measured synaptic physiology 28 and transcriptomes in the hippocampus. These datasets entailed 290,850 behavioral measures in 2,770 mice, 51,048 measures of electrophysiology in 2,836 hippocampal slices, and genome-wide transcriptome analysis on 390 mice, representing the largest genetic study of mammalian synapses to date.…”

“…All datasets are freely available at the Genes to Cognition (G2C) Programme database http://www.genes2cognition.org/publications/g2c/. Here, we report the genetic dissection of the behavioral repertoire and in a companion manuscript we report the genetic dissection of synaptic electrophysiology and integration with behavioral data 28 .…”

A lifespan program of mouse synaptome architecture

“…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).…”