Distinct kinetics of synaptic structural plasticity, memory formation, and memory decay in massed and spaced learning

Abstract

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...

Modeling memory consolidation during posttraining periods in cerebellovestibular learning

“…In Pavlovian eyeblink conditioning, a conditioned response seems to be consolidated in the cerebellar cortex (29)(30)(31)(32). Even in OKR adaptation, a trace of long-term memory remains in the cerebellar cortex as the decrease in the number of PF-PC synapses (33,34), which might represent eye movement trajectory or information on OKR phase (35)(36)(37). Moreover, consolidation of motor memory in general should be investigated in depth from reflex to voluntary movement, particularly in primates including humans.…”

IP3 receptor mutations and brain diseases in human and rodents

“…However, recent studies also suggest changes in spine density in PCs following cerebellar motor learning (Aziz et al . ; Wang et al . ).…”

Regulation of spinogenesis in mature Purkinje cells via mGluR/PKC-mediated phosphorylation of CaMKIIβ

“…Whereas a close link between spine structural rearrangement caused by synaptic plasticity and learning/memory has been thoroughly studied, particularly in cortical and hippocampal neurons (48,49), a previous study has suggested that spine morphology on distal branches of Purkinje cells is not affected by induction of parallel fiber-Purkinje cell LTD (50). However, recent studies have also demonstrated that cerebellar motor learning decreases spine density in Purkinje cells (8,9). Although a molecular mechanism of spine plasticity in Purkinje cells associated with long-term motor learning is unknown, our findings, at least in part, could provide a potential molecular mechanism that links synaptic inputs to spine structural plasticity in Purkinje cells.…”

“…Spine density and morphology of Purkinje cells change significantly during development (3, 4), and morphological abnormalities of spines are closely associated with many neurological disorders (5-7). Recent studies also demonstrated that some forms of training for cerebellar motor learning results in altered spine density in Purkinje cells (8,9). Thus, maintenance of proper spine density and morphology of Purkinje cells is a critical aspect of cerebellar functions.…”