Publications by authors named "Heike Blockus"

The incorporation of new information into the hippocampal network is likely to be constrained by its innate architecture and internally generated activity patterns. However, the origin, organization and consequences of such patterns remain poorly understood. In the present study we show that hippocampal network dynamics are affected by sequential neurogenesis.

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Dendritic calcium signaling is central to neural plasticity mechanisms that allow animals to adapt to the environment. Intracellular calcium release (ICR) from the endoplasmic reticulum has long been thought to shape these mechanisms. However, ICR has not been investigated in mammalian neurons in vivo.

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The hippocampus plays a critical role in memory consolidation, mediated by coordinated network activity during sharp-wave ripple (SWR) events. Despite the link between SWRs and hippocampal plasticity, little is known about how network state affects information processing in dendrites, the primary sites of synaptic input integration and plasticity. Here, we monitored somatic and basal dendritic activity in CA1 pyramidal cells in behaving mice using longitudinal two-photon calcium imaging integrated with simultaneous local field potential recordings.

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Hippocampal place cells underlie spatial navigation and memory. Remarkably, CA1 pyramidal neurons can form new place fields within a single trial by undergoing rapid plasticity. However, local feedback circuits likely restrict the rapid recruitment of individual neurons into ensemble representations.

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Local circuit architecture facilitates the emergence of feature selectivity in the cerebral cortex. In the hippocampus, it remains unknown whether local computations supported by specific connectivity motifs regulate the spatial receptive fields of pyramidal cells. Here we developed an in vivo electroporation method for monosynaptic retrograde tracing and optogenetics manipulation at single-cell resolution to interrogate the dynamic interaction of place cells with their microcircuitry during navigation.

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Synaptic connectivity within adult circuits exhibits a remarkable degree of cellular and subcellular specificity. We report that the axon guidance receptor Robo2 plays a role in establishing synaptic specificity in hippocampal CA1. In vivo, Robo2 is present and required postsynaptically in CA1 pyramidal neurons (PNs) for the formation of excitatory (E) but not inhibitory (I) synapses, specifically in proximal but not distal dendritic compartments.

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Synaptic connectivity within neural circuits is characterized by high degrees of cellular and subcellular specificity. This precision arises from the combined action of several classes of molecular cues, transmembrane receptors, secreted cues and extracellular matrix components, coordinating transitions between axon guidance, dendrite patterning, axon branching and synapse specificity. We focus this review on recent insights into some of the molecular and cellular mechanisms controlling these transitions and present the results of large-scale efforts and technological developments aimed at mapping neural connectivity at single cell resolution in the mouse cortex as a mammalian model organism.

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The balance between excitatory and inhibitory (E and I) synapses is thought to be critical for information processing in neural circuits. However, little is known about the spatial principles of E and I synaptic organization across the entire dendritic tree of mammalian neurons. We developed a new open-source reconstruction platform for mapping the size and spatial distribution of E and I synapses received by individual genetically-labeled layer 2/3 (L2/3) cortical pyramidal neurons (PNs) in vivo.

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Control of microtubule (MT) nucleation and dynamics is critical for neuronal function. Whether MT nucleation is regulated at presynaptic boutons and influences overall presynaptic activity remains unknown. By visualizing MT plus-end dynamics at individual excitatory en passant boutons in axons of cultured hippocampal neurons and in hippocampal slices expressing EB3-EGFP and vGlut1-mCherry, we found that dynamic MTs preferentially grow from presynaptic boutons, show biased directionality in that they are almost always oriented toward the distal tip of the axon, and can be induced by neuronal activity.

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Understanding the mechanisms establishing the complex but precise pattern of connectivity characterizing neural circuits remains an immense challenge. In a recent issue of Neuron, Mao and colleagues (2018) provide new insights by showing that the activation kinetics of EphB2, a transmembrane receptor tyrosine kinase, control whether dendritic filopodia makes a synapse with candidate axons.

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During the development of the central nervous system (CNS), only motor axons project into peripheral nerves. Little is known about the cellular and molecular mechanisms that control the development of a boundary at the CNS surface and prevent CNS neuron emigration from the neural tube. It has previously been shown that a subset of spinal cord commissural axons abnormally invades sensory nerves in hypomorphic embryos and knockouts.

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Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes.

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The modular reiterative pattern of the fly visual system makes it an ideal model to study axon guidance and synaptogenesis. In this issue of Neuron, Tadros et al. (2016) show that Dscam2/4 promote the anchoring of dendrites to their targets.

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Notch signaling is altered in many cancers. Our previous findings in primary pediatric ependymoma support a role for NOTCH in glial oncogenesis. The present study evaluates the γ-secretase inhibitor RO4929097 in glial tumor models.

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Development of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain.

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Focal adhesion (FA) kinase (FAK) regulates cell survival and motility by transducing signals from membrane receptors. The C-terminal FA targeting (FAT) domain of FAK fulfils multiple functions, including recruitment to FAs through paxillin binding. Phosphorylation of FAT on Tyr(925) facilitates FA disassembly and connects to the MAPK pathway through Grb2 association, but requires dissociation of the first helix (H1) of the four-helix bundle of FAT.

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Slit repulsion, mediated by Robo receptors, is known to play a major role in axon guidance in the nervous system. However, recent studies have revealed that in the mammalian cortex these molecules are highly versatile and that their function extends far beyond axon guidance. They act at all phases of development to control neurogenesis, neuronal migration, axon patterning, dendritic outgrowth and spinogenesis.

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In this issue of Neuron, Wright et al. (2012) identify two novel mediators of α-dystroglycan glycosylation in mouse and unravel a novel function of glycosylated dystroglycan in axon guidance by providing evidence for direct binding of α-DG to the midline chemorepellent Slit2.

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A homogeneous fluorescence resonance energy transfer (FRET) system for the real-time monitoring of exchange factor-catalyzed activation of a ras-like small GTPase is described. The underlying design is based on supramolecular template effects exerted by protein-protein interactions between the GTPase adenosine diphosphate ribosylation factor (ARF) and its effector protein GGA3. The GTPase is activated when bound to guanosine triphosphate (GTP) and switched off in its guanosine diphosphate (GDP)-bound state.

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Virtual screening (VS) of chemical libraries formatted in silico provides an alternative to experimental high-throughput screening (HTS) for the identification of small molecule modulators of protein function. We have tailored a VS approach combining fingerprint similarity searching and support vector machine modeling toward the identification of small molecular probes for the study of cytohesins, a family of cytoplasmic regulator proteins with multiple cellular functions. A total of 40 new structurally diverse inhibitors were identified, and 26 of these compounds were more active than the primary VS template, a single known inhibitory chemotype, in at least one of three different assays (guanine nucleotide exchange, Drosophila insulin signaling, and human leukocyte cell adhesion).

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