Glial modulation of the parallel memory formation.

Actions from glial cells could affect the readiness and efficacy of learning and memory. Using a mouse cerebellar-dependent horizontal optokinetic response motor learning paradigm, short-term memory (STM) formation during the online training period and long-term memory (LTM) formation during the offline rest period were studied. A large variability of online and offline learning efficacies was found. The early bloomers with booming STM often had a suppressed LTM formation and late bloomers with no apparent acute training effect often exhibited boosted offline learning performance. Anion channels containing LRRC8A are known to release glutamate. Conditional knockout of LRRC8A specifically in astrocytes including cerebellar Bergmann glia resulted in a complete loss of STM formation while the LTM formation during the rest period remained. Optogenetic manipulation of glial activity by channelrhodopsin-2 or archaerhodopsin-T (ArchT) during the online training resulted in enhancement or suppression of STM formation, respectively. STM and LTM are likely to be triggered simultaneously during online training, but LTM is expressed later during the offline period. STM appears to be volatile and the achievement during the online training is not handed over to LTM. In addition, we found that glial ArchT photoactivation during the rest period resulted in the augmentation of LTM formation. These data suggest that STM formation and LTM formation are parallel separate processes. Strategies to weigh more on the STM or the LTM could depend on the actions of the glial cells.

Intrinsic Plasticity of Cerebellar Purkinje Cells Contributes to Motor Memory Consolidation.

Intrinsic plasticity of cerebellar Purkinje cells (PCs) has recently been demonstrated in cerebellar local circuits; however, its physiological impact on cerebellar learning and memory remains elusive. Here, we suggest that intrinsic plasticity of PCs is tightly involved in motor memory consolidation based on findings from PC-specific STIM1 knockout male mice, which show severe memory consolidation deficiency in vestibulo-ocular reflex memory. Gain-up training of the vestibulo-ocular reflex produced a decrease in the synaptic weight of PCs in both the WT and KO groups. However, intrinsic plasticity was impaired only in the knockout mice. Furthermore, the observed defects in the intrinsic plasticity of PCs led to the formation of aberrant neural plasticity in the vestibular nucleus neurons. Our results suggest that synergistic modulation of intrinsic and synaptic plasticity in PCs is required for the changes in downstream plasticity in the vestibular nucleus, and thereby contributing to the long-term storage of motor memory.SIGNIFICANCE STATEMENT Synaptic plasticity is a well-known mechanism for learning and memory. Although plasticity of excitability, intrinsic plasticity, of the cerebellar Purkinje cell has been reported in both directions (potentiation and depression), the physiological role of intrinsic plasticity still remains ambiguous. In this study, we suggest that both synaptic and intrinsic plasticity are required for successful memory consolidation in cerebellar eye movement learning. Despite successful induction and maintenance of synaptic plasticity, we found deficits of memory consolidation when there were defects in intrinsic plasticity. Our results suggest that intrinsic plasticity of cerebellar Purkinje cell has a significant role in motor memory consolidation.

The Concept of Transmission Coefficient Among Different Cerebellar Layers: A Computational Tool for Analyzing Motor Learning.

High-fidelity regulation of information transmission among cerebellar layers is mainly provided by synaptic plasticity. Therefore, determining the regulatory foundations of synaptic plasticity in the cerebellum and translating them to behavioral output are of great importance. To date, many experimental studies have been carried out in order to clarify the effect of synaptic defects, while targeting a specific signaling pathway in the cerebellar function. However, the contradictory results of these studies at the behavioral level further add to the ambiguity of the problem. Information transmission through firing rate changes in populations of interconnected neurons is one of the most widely accepted principles of neural coding. In this study, while considering the efficacy of synaptic interactions among the cerebellar layers, we propose a firing rate model to realize the concept of transmission coefficient. Thereafter, using a computational approach, we test the effect of different values of transmission coefficient on the gain adaptation of a cerebellar-dependent motor learning task. In conformity with the behavioral data, the proposed model can accurately predict that disruption in different forms of synaptic plasticity does not have the same effect on motor learning. Specifically, impairment in training mechanisms, like in the train-induced LTD in parallel fiber-Purkinje cell synapses, has a significant negative impact on all aspects of learning, including memory formation, transfer, and consolidation, although it does not disrupt basic motor performance. In this regard, the overinduction of parallel fiber-molecular layer interneuron LTP could not prevent motor learning impairment, despite its vital role in preserving the robustness of basic motor performance. In contrast, impairment in plasticity induced by interneurons and background activity of climbing fibers is partly compensable through overinduction of train-induced parallel fiber-Purkinje cell LTD. Additionally, blockade of climbing fiber signaling to the cerebellar cortex, referred to as olivary system lesion, shows the most destructive effect on both motor learning and basic motor performance. Overall, the obtained results from the proposed computational framework are used to provide a map from procedural motor memory formation in the cerebellum. Certainly, the generalization of this concept to other multi-layered networks of the brain requires more physiological and computational researches.

Chloride Homeostasis in Neurons With Special Emphasis on the Olivocerebellar System: Differential Roles for Transporters and Channels.

The intraneuronal ionic composition is an important determinant of brain functioning. There is growing evidence that aberrant homeostasis of the intracellular concentration of Cl- ([Cl-]i) evokes, in addition to that of Na+ and Ca2+, robust impairments of neuronal excitability and neurotransmission and thereby neurological conditions. More specifically, understanding the mechanisms underlying regulation of [Cl-]i is crucial for deciphering the variability in GABAergic and glycinergic signaling of neurons, in both health and disease. The homeostatic level of [Cl-]i is determined by various regulatory mechanisms, including those mediated by plasma membrane Cl- channels and transporters. This review focuses on the latest advances in identification, regulation and characterization of Cl- channels and transporters that modulate neuronal excitability and cell volume. By putting special emphasis on neurons of the olivocerebellar system, we establish that Cl- channels and transporters play an indispensable role in determining their [Cl-]i and thereby their function in sensorimotor coordination.

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

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.