Spine head calcium as a measure of summed postsynaptic activity for driving synaptic plasticity

We use a computational model of a hippocampal CA1 pyramidal cell to demonstrate that spine head calcium provides an instantaneous readout at each synapse of the postsynaptic weighted sum of all presynaptic activity impinging on the cell. The form of the readout is equivalent to the functions of weighted, summed inputs used in neural network learning rules. Within a dendritic layer, peak spine head calcium levels are either a linear or sigmoidal function of the number of coactive synapses, with nonlinearity depending on the ability of voltage spread in the dendrites to reach calcium spike threshold. This is strongly controlled by the potassium A-type current, with calcium spikes and the consequent sigmoidal increase in peak spine head calcium present only when the A-channel density is low. Other membrane characteristics influence the gain of the relationship between peak calcium and the number of active synapses. In particular, increasing spine neck resistance increases the gain due to increased voltage responses to synaptic input in spine heads. Colocation of stimulated synapses on a single dendritic branch also increases the gain of the response. Input pathways cooperate: CA3 inputs to the proximal apical dendrites can strongly amplify peak calcium levels due to weak EC input to the distal dendrites, but not so strongly vice versa. CA3 inputs to the basal dendrites can boost calcium levels in the proximal apical dendrites, but the relative electrical compactness of the basal dendrites results in the reverse effect being less significant. These results give pointers as to how to better describe the contributions of pre- and postsynaptic activity in the learning "rules" that apply in these cells. The calcium signal is closer in form to the activity measures used in traditional neural network learning rules than to the spike times used in spike-timing-dependent plasticity.Output Type: Lette

Contributions to models of single neuron computation in striatum and cortex

A deeper understanding is required of how a single neuron utilizes its nonlinear subcellular devices to generate complex neuronal dynamics. Two compartmental models of cortex and striatum are accurately formulated and firmly grounded in the experimental reality of electrophysiology to address the questions: how striatal projection neurons implement location-dependent dendritic integration to carry out association-based computation and how cortical pyramidal neurons strategically exploit the type and location of synaptic contacts to enrich its computational capacities.Neuronale Zellen transformieren kontinuierliche Signale in diskrete Zeitserien von Aktionspotentialen und kodieren damit Perzeptionen und interne Zustände. Kompartiment-Modelle werden formuliert von Nervenzellen im Kortex und Striatum, die elektrophysiologisch fundiert sind, um spezifische Fragen zu adressieren: i) Inwiefern implementieren Projektionen vom Striatum ortsabhängige dendritische Integration, um Assoziationens-basierte Berechnungen zu realisieren? ii) Inwiefern nutzen kortikale Zellen den Typ und den Ort, um die durch sie realisierten Berechnungen zu optimieren

Synaptic nanomodules underlie the organization and plasticity of spine synapses.

Experience results in long-lasting changes in dendritic spine size, yet how the molecular architecture of the synapse responds to plasticity remains poorly understood. Here a combined approach of multicolor stimulated emission depletion microscopy (STED) and confocal imaging in rat and mouse demonstrates that structural plasticity is linked to the addition of unitary synaptic nanomodules to spines. Spine synapses in vivo and in vitro contain discrete and aligned subdiffraction modules of pre- and postsynaptic proteins whose number scales linearly with spine size. Live-cell time-lapse super-resolution imaging reveals that NMDA receptor-dependent increases in spine size are accompanied both by enhanced mobility of pre- and postsynaptic modules that remain aligned with each other and by a coordinated increase in the number of nanomodules. These findings suggest a simplified model for experience-dependent structural plasticity relying on an unexpectedly modular nanomolecular architecture of synaptic proteins

Activity-driven formation and stabilization of functional spine synapses

Physical changes in neuronal connections, dictated by the neuronal network activity, are believed to be essential for learning and memory. Long-term potentiation (LTP) of synaptic transmission has emerged as a model to study activity-driven plasticity. The majority of excitatory contacts between neurons, called synapses, are found on spines, small dendritic protrusions. LTP is known to trigger the formation and stabilization of new dendritic spines in vitro. Similarly, experience-dependent plasticity in vivo is associated with changes in the number and stability of spines. However, to date, the contribution of excitatory synaptogenesis to the enhanced synaptic transmission after LTP remains elusive. Do new spines form functional synapses with the inputs stimulated during LTP induction and thereby follow Hebbian co-activation rules, or do they connect with random partners? Furthermore, at which time-point are de novo spines functionally integrated into the network? I developed an optical approach to stably and exclusively stimulate the axons of a defined channelrhodopsin-2 (ChR2)-transduced subset of CA3 cell in mature hippocampal slice culture over extended periods of time (up to 24h). I continuously monitored synaptic activation and synaptic structure of CA1 cells dendrites using two-photon imaging. To control the dendritic location where LTP and associated spinogenesis were allowed to take place, I globally blocked Na+-dependent action potential firing and directly evoke neurotransmitter release by local light-evoked depolarization of ChR2-expressing presynaptic boutons (in TTX, 4-AP). I induced optical LTP specifically at this location by combining optogenetic activation with chemical pairing (in low [Mg2+]o, high [Ca2+]o, forskolin, and rolipram). Taking advantage of the NMDA-receptor mediated calcium influx during synaptic activation I assessed the formation of functional synapses using the genetically encoded calcium indicator GCaMP6s. I find that optical LTP led to the generation of new spines, decreased the stability of preexisting spines and increased the stability of new spines. Under optical LTP conditions, a fraction of new spines responded to optical presynaptic stimulation within hours after formation. However, the occurrence of the first synaptic calcium response in de novo spines varied considerably, ranging from 8.5 min to 25 h. Most new spines became responsive within 4 h (1.2 ± 0.9 h, mean ± S.D., n = 16 out of 20), whereas the remainder showed their first response only on the second experimental day (18.2 ± 3.7 h). Importantly, new spines generated under optical LTP were more likely to build functional synapses with light-activated, ChR2-expressing axons than spontaneously formed spines (new responsive spines under optical LTP: 64 ± 4 %; control 1: 0%; control 2: 13 ± 4 %; control 3: 11 ± 4 %). Furthermore, new spines that were responsive to optical presynaptic stimulation were less prone to be eliminated after overnight incubation than new spines that failed to respond (% overnight spine survival; 81 ± 3 % new responsive spines; 58 ± 4 % of new unresponsive spines). In summary, the results from my thesis demonstrate that synapses can form rapidly in an input-specific manner

Long-Term Relationships between Synaptic Tenacity, Synaptic Remodeling, and Network Activity

Long term time-lapse imaging reveals that individual synapses undergo significant structural remodeling not only when driven by activity, but also when network activity is absent, raising questions about how reliably individual synapses maintain connections

Coordinated structural plasticity across synapses in the adult hippocampus

textNeural circuitry is determined primarily by trillions of synaptic junctions that link cells in the nervous system. Understanding how the structure of the synapse influences its function has been a central goal of cellular neuroscience since synapses were first recognized more than a century ago. Long-term potentiation (LTP), a long lasting enhancement of synaptic efficacy, is a well-characterized cellular correlate of learning and memory that results in dramatic structural remodeling of the synapse. Research has focused heavily on the postsynaptic structural remodeling that occurs to support LTP, but concomitant presynaptic and subcellular remodeling during LTP has been left largely unexplored. To address these questions, three-dimensional reconstructions from serial section electron microscopy of presynaptic boutons, vesicle pools, and dendritic smooth endoplasmic reticulum (SER) in hippocampal area CA1 were created and quantified. The data presented in this dissertation demonstrate that coordinated structural plasticity occurs at both pre- and postsynaptic sides of adult hippocampal synapses by 2 hours during LTP induced with theta burst stimulation. Presynaptically, the number of presynaptic boutons correlated perfectly with fewer dendritic spines during LTP that were previously reported, suggesting that synaptic units act as cohesive structures. Vesicle pools were mobilized and vesicle transport packets were moved into boutons or were released in transit. Dendritic SER is a ubiquitous intracellular membranous network involved in calcium signaling and protein modification. The complexity of SER influences the movement of diffusible membrane cargo. SER was dramatically remodeled during LTP, redistributing from the shaft of the dendrite into spines and becoming highly complex near synapses that were largest during LTP. As a preliminary investigation into how normal mechanisms of structural plasticity described in this dissertation might go awry under conditions of synaptic pathology, three-dimensional reconstructions of CA1 synaptic ultrastructure in a mouse model of Fragile X, which is known to express exaggerated mGluR-dependent long-term depression (LTD), were created and quantified. Synaptic ultrastructure was similar with that of the wild-type mouse, suggesting that structural malformation in FX might be confined to development or to other brain regions.Neuroscienc