CYFIP2 is thought to regulate mRNA translation at synapses. Tiwari et al . reveal reduced CYFIP2 expression in post-mortem Alzheimer’s disease brains, and show that CYFIP2 reduction in mice causes abnormal amyloid production, tau hyperphosphorylation, and spatial memory loss. CYFIP2 could represent a molecular ‘hub’ with potential as a therapeutic target in Alzheimer’s disease.

Cerebellar motor learning is suggested to be caused by long-term plasticity of excitatory parallel fiber-Purkinje cell (PF-PC) synapses associated with changes in the number of synaptic AMPA-type glutamate receptors (AMPARs). However, whether the AMPARs decrease or increase in individual PF-PC synapses occurs in physiological motor learning and accounts for memory that lasts over days remains elusive. We combined quantitative SDS-digested freeze-fracture replica labeling for AMPAR and physical dissector electron microscopy with a simple model of cerebellar motor learning, adaptation of horizontal optokinetic response (HOKR) in mouse. After 1-h training of HOKR, short-term adaptation (STA) was accompanied with transient decrease in AMPARs by 28% in target PF-PC synapses. STA was well correlated with AMPAR decrease in individual animals and both STA and AMPAR decrease recovered to basal levels within 24 h. Surprisingly, long-term adaptation (LTA) after five consecutive daily trainings of 1-h HOKR did not alter the number of AMPARs in PF-PC synapses but caused gradual and persistent synapse elimination by 45%, with corresponding PC spine loss by the fifth training day. Furthermore, recovery of LTA after 2 wk was well correlated with increase of PF-PC synapses to the control level. Our findings indicate that the AMPARs decrease in PF-PC synapses and the elimination of these synapses are in vivo engrams in short-and long-term motor learning, respectively, showing a unique type of synaptic plasticity that may contribute to memory consolidation.long-term depression | high-voltage electron microscope | Golgi staining I mage stabilization in the visual field via the vestibulo-ocular reflex and optokinetic response requires accurate extraocular muscle synergies that rely on long-term plastic calibrations in the cerebellar flocculus (FL) and its downstream target vestibular nuclei (VN) (1-8). Long-term depression (LTD) in parallel fiber-Purkinje cell (PF-PC) synapses has been postulated as a possible mechanism for this plastic calibration based on many lines of mutant mice that lack both LTD and learning (9-12). However, LTD's role in motor learning has been recently questioned by a few mutant mice lines (13) and mice with pharmacological treatments (14) that showed lack of LTD but no impairment of learning. Furthermore, long-term potentiation in PF-PC synapses has been also shown to be involved in the motor learning (15). Recent evidence indicates that various forms of synaptic plasticity works synergistically and can compensate each other when one is missing in cerebellar motor learning (16). Despite the apparently contradictory results, no direct evidence for the decrease or increase of synaptic AMPA receptors (AMPARs) has been shown in physiological motor learning. To elucidate in vivo neuronal substrates for motor learning in wildtype mouse, we examined individual PF-PC synapses using quantitative SDS-digested freeze-fracture replica labeling (SDS-FRL) (17) combined with morphometric EM analysis after adaptation of ho...

Long-lasting memories are formed when the stimulus is temporally distributed (spacing effect). However, the synaptic mechanisms underlying this robust phenomenon and the precise time course of the synaptic modifications that occur during learning remain unclear. Here we examined the adaptation of horizontal optokinetic response in mice that underwent 1 h of massed and spaced training at varying intervals. Despite similar acquisition by all training protocols, 1 h of spacing produced the highest memory retention at 24 h, which lasted for 1 mo. The distinct kinetics of memory are strongly correlated with the reduction of floccular parallel fiber-Purkinje cell synapses but not with AMPA receptor (AMPAR) number and synapse size. After the spaced training, we observed 25%, 23%, and 12% reduction in AMPAR density, synapse size, and synapse number, respectively. Four hours after the spaced training, half of the synapses and Purkinje cell spines had been eliminated, whereas AMPAR density and synapse size were recovered in remaining synapses. Surprisingly, massed training also produced long-term memory and halving of synapses; however, this occurred slowly over days, and the memory lasted for only 1 wk. This distinct kinetics of structural plasticity may serve as a basis for unique temporal profiles in the formation and decay of memory with or without intervals. cerebellar motor learning | AMPA receptor reduction | synapse shrinkage and elimination D uring learning, memories are formed in a specific population of neuronal circuits and are consolidated for persistence (1, 2). These memory processes are supported by discrete subcellular events such as reversible modifications in the efficacy of synaptic transmission (3-5) or persistent structural modifications in the size and number of synaptic connections (6-8). However, how these synaptic modifications relate to the dynamics of formation and decay of memories in behaving animals remains elusive. Memory formation and its persistence are also sensitive to the temporal features of stimulus presentation, as observed in the well-known "spacing effect." Training trials that include resting intervals between them (spaced training) produce stronger and longer-lasting memories than do the same number of trials with no intervals (massed training) (9). The spacing effect has been observed in a variety of explicit and implicit memory tasks (10-13), and the molecular mechanisms supporting this phenomenon have been reported (14-18). Various intracellular signaling molecules such as CREB (19), mitogen-activated protein (MAP) kinase (20, 21), and PKA (22, 23) underlie the spacing effect and are implicated in the remodeling of neuronal structures (23). In vitro studies showed that spaced stimuli induced the protrusion of new filopodia (20) and the recruitment of new synapses (24) in hippocampal neurons. However, despite the existence of numerous behavioral and molecular studies, no conjoint study has elucidated the synaptic correlates that underpin the expression of the spacing effect du...