Methamphetamine learning induces persistent nonmuscle myosin II-dependent spine motility in the basolateral amygdala

Abstract

Nonmuscle myosin II inhibition (NMIIi) in the basolateral amygdala (BLA) selectively disrupts memories associated with methamphetamine (METH) days after learning, without retrieval.However, the molecular mechanisms underlying this selective vulnerability remain poorly understood. A known function of NMII is to transiently activate dendritic spine actin dynamics with learning. Therefore, we hypothesized that METH-associated learning perpetuates NMIIdriven actin dynamics in dendritic spines, leading to an extended window of vulnerability for memory disruption. Two-photon imaging of actin-mediated spine motility in neurons from memory-related structures, BLA and CA1, revealed a persistent increase in spine motility after METH-associated learning that was restricted to BLA neurons. METH-induced changes to BLA spine dynamics were reversed by a single systemic injection of an NMII inhibitor. Thus, a perpetual form of NMII-driven spine actin dynamics in BLA neurons may contribute to the unique susceptibility of METH-associated memories.Dendritic spines are small, actin-rich structures lining dendrites of excitatory neurons.These postsynaptic compartments are dynamic and enable input-specific biochemical and electrical isolation of synapses to facilitate signal transduction and information storage (1-3).During learning, dendritic spines undergo both structural and functional changes to stabilize synapses and, ultimately, memory (4, 5). Consistent with this, there is a tight connection between the physical geometry of spines and the ability to transform experiences into long-term memory (6-8). Polymerization of actin, the elongation and complex branching of filamentous actin (F-actin), drives the spine structural plasticity that is required for functional plasticity and learning (9-14).Interestingly, long-term potentiation (LTP) and newly formed memories become impervious to actin depolymerization shortly after the underlying synaptic plasticity occurs (15)(16)(17). This is attributed to rapid stabilization of the actin cytoskeleton through the cessation of polymerization and recruitment of actin capping and stabilizing proteins (18). However, we recently made the unexpected discovery that memories associated with the commonly abused stimulant, methamphetamine (METH), remain uniquely susceptible to actin depolymerization many days after learning (19). Indeed, a single infusion of the actin depolymerizer, Latrunculin A (LatA) into the basolateral amygdala (BLA) results in an immediate, long-lasting and retrievalindependent loss of the METH-associated memory and associated drug seeking behavior.Furthermore, this memory loss is accompanied by a return of BLA spine density to pre-METH conditioning levels. LatA works by sequestering actin monomers, removing them from the pool available for addition to F-actin during polymerization (20,21). In this way, LatA influences populations of dynamic, but not stable, actin. Thus the susceptibility of a METH-associated memory days after learning suggests that METH may interfere with the ...