Synaptic plasticity during systems memory consolidation

After learning, memory is initially encoded in the hippocampus but subsequently stabilized in other brain regions such as the cortex for long-lasting storage. This process is known as systems memory consolidation, and its cellular mechanism has long been a fundamental question. Synaptic plasticity is the major cellular mechanism underlying learning and memory, and is therefore considered a key function in the process of systems memory consolidation. Therefore, many studies have aimed to establish a causal link between synaptic plasticity in the brain and memory-associated behaviors. In this review, I discuss the various lines of research showing the function of synaptic plasticity, mainly in the hippocampus and cortex during memory consolidation

Geometric principles of second messenger dynamics in dendritic spines.

Dendritic spines are small, bulbous protrusions along dendrites in neurons and play a critical role in synaptic transmission. Dendritic spines come in a variety of shapes that depend on their developmental state. Additionally, roughly 14-19% of mature spines have a specialized endoplasmic reticulum called the spine apparatus. How does the shape of a postsynaptic spine and its internal organization affect the spatio-temporal dynamics of short timescale signaling? Answers to this question are central to our understanding the initiation of synaptic transmission, learning, and memory formation. In this work, we investigated the effect of spine and spine apparatus size and shape on the spatio-temporal dynamics of second messengers using mathematical modeling using reaction-diffusion equations in idealized geometries (ellipsoids, spheres, and mushroom-shaped). Our analyses and simulations showed that in the short timescale, spine size and shape coupled with the spine apparatus geometries govern the spatiotemporal dynamics of second messengers. We show that the curvature of the geometries gives rise to pseudo-harmonic functions, which predict the locations of maximum and minimum concentrations along the spine head. Furthermore, we showed that the lifetime of the concentration gradient can be fine-tuned by localization of fluxes on the spine head and varying the relative curvatures and distances between the spine apparatus and the spine head. Thus, we have identified several key geometric determinants of how the spine head and spine apparatus may regulate the short timescale chemical dynamics of small molecules that control synaptic plasticity

Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging.

Localization of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIα (α) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIβ (β). The βE' splice variant bound more weakly than α, showing that binding by β depends critically on the interdomain linker. The mutations βT287D and αT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (βK43R and αK42M) or Ca(2+)/calmodulin (βA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the αT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIα isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar) monovalent interaction

Storage of spatiotemporal input sequences in dendrites of pyramidal neurons

Plastic changes in neurons are widely considered to underpin the formation and maintenance of memory. The mechanisms of induction and expression of plasticity are, therefore, crucial to our understanding of the capacity of information storage that neurons possess. Using two-photon glutamate uncaging and whole-cell electrophysiological recordings, I demonstrate that dendrites of neurons are capable of preferentially storing specific spatiotemporal sequences, and describe the physiological properties of this new form of plasticity. Such plastic changes are dependent on Ca2+ influx through NMDA receptors, which is consistent with previous reports regarding induction of potentiation. Using two-photon Ca2+ imaging, I demonstrate that spatiotemporal plasticity is a result of a distinct homogeneous spatial increase in Ca2+ influx of different spatiotemporal sequences. Using the NEURON simulation environment, I used my experimental findings to perform simulations of synaptic plasticity rules. I found that homogeneous increases in synaptic strength across the dendrite can result in the spatiotemporal plasticity that I empirically observed. Moreover, I employed a genetic optimization algorithm and parallelized simulations to show that such changes are within physiological parameters observed in cortical neurons. My PhD therefore describes a novel form of plasticity, and proposes that dendrites are capable of more extensive information storage than was previously assumed

Pyk2 in the amygdala modulates chronic stress sequelae via PSD-95-related micro-structural changes

Major depressive disorder (MDD) is a common disorder with a variety of symptoms including mood alterations, anhedonia, sleep and appetite disorders, and cognitive disturbances. Stressful life events are among the strongest risk factors for developing MDD. At the cellular level, chronic stress results in the modification of dendritic spine morphology and density. Here, we study the role of Pyk2 in the development of depressive-like symptoms induced by a model of chronic unpredictable mild stress (CUMS). Pyk2 is a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the forebrain principal neurons and involved in spine structure and density regulation. We show that Pyk2 knockout mice are less affected to anxiety-like and anhedonia-like phenotypes induced by the CUMS paradigm. Using region-specific knockout, we demonstrate that this phenotype is fully recapitulated by selective Pyk2 inactivation in the amygdala. We also show that in the absence of Pyk2 the spine alterations, PSD-95 clustering, and NMDA receptors changes induced by the CUMS paradigm are prevented. Our results reveal a possible role for Pyk2 in the response to stress and in synaptic markers expression and spine density regulation in the amygdala. We suggest that Pyk2 contributes to stress-induced responses through micro-structural changes and that its deficit may contribute to the resilience to chronic stress

The dendritic engram

Accumulating evidence from a wide range of studies, including behavioral, cellular, molecular and computational findings, support a key role of dendrites in the encoding and recall of new memories. Dendrites can integrate synaptic inputs in non-linear ways, provide the substrate for local protein synthesis and facilitate the orchestration of signaling pathways that regulate local synaptic plasticity. These capabilities allow them to act as a second layer of computation within the neuron and serve as the fundamental unit of plasticity. As such, dendrites are integral parts of the memory engram, namely the physical representation of memories in the brain and are increasingly studied during learning tasks. Here, we review experimental and computational studies that support a novel, dendritic view of the memory engram that is centered on non-linear dendritic branches as elementary memory units. We highlight the potential implications of dendritic engrams for the learning and memory field and discuss future research directions