Abstract
It is well established that the efficacy of synaptic connections can be rapidly modified by neural activity, yet how the environment and prior experience modulate such synaptic and behavioral plasticity is only beginning to be understood. Here we show in C. elegans that the broadly conserved scaffolding molecule MAGI-1 is required for the plasticity observed in a glutamatergic circuit. This mechanosensory circuit mediates reversals in locomotion in response to touch stimulation, and the AMPA-type receptor (AMPAR) subunits GLR-1 and GLR-2, which are required for reversal behavior, are localized to ventral cord synapses in this circuit. We find that animals modulate GLR-1 and GLR-2 localization in response to prior mechanosensory stimulation; a specific isoform of MAGI-1 (MAGI-1L) is critical for this modulation. We show that MAGI-1L interacts with AMPARs through the intracellular domain of the GLR-2 subunit, which is required for the modulation of AMPAR synaptic localization by mechanical stimulation. In addition, mutations that prevent the ubiquitination of GLR-1 prevent the decrease in AMPAR localization observed in previously stimulated magi-1 mutants. Finally, we find that previously-stimulated animals later habituate to subsequent mechanostimulation more rapidly compared to animals initially reared without mechanical stimulation; MAGI-1L, GLR-1, and GLR-2 are required for this change in habituation kinetics. Our findings demonstrate that prior experience can cause long-term alterations in both behavioral plasticity and AMPAR localization at synapses in an intact animal, and indicate a new, direct role for MAGI/S-SCAM proteins in modulating AMPAR localization and function in the wake of variable sensory experience.
Highlights
Experience leads to learning and memory formation through changes in the strength of connectivity between neurons
C. elegans exhibit a form of long-term memory in response to repetitive mechanical stimulation that requires GLR-1 [19]; we find that both GLR-2 and MAGI-1L mutants share a similar defect in long-term memory acquisition
We identified a specific isoform of MAGI-1 as a novel regulator of experience-dependent plasticity and AMPA-type receptor (AMPAR) trafficking
Summary
Experience leads to learning and memory formation through changes in the strength of connectivity between neurons (synaptic plasticity). The regulated trafficking of AMPARs at synapses is an important mechanism for achieving synaptic plasticity [1,2]. The molecular mechanisms that mediate synaptic plasticity are beginning to be elucidated; many of the key components involved are synaptic scaffolding molecules of the membrane-associated guanylate kinase (MAGUK) family such as PSD-95 and PSD-93 [1,2]. MAGI-2 ( called synaptic scaffolding molecule, or S-SCAM) has been shown to interact with NMDA receptors at excitatory synapses [4]. This member of the MAGI subfamily of MAGUKs has three splice variants: a, b, and c [6]. Mammalian MAGI-2 has been shown to interact with a great variety of post-synaptic density proteins; little is known about the precise function of MAGI-2 at excitatory synapses
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