Biology subjects

D'Angelo, E.

Publications and source records attributed to D'Angelo, E..

25 records · Page 2Linked to original sources

bioRxiv2019

Calcium channel-dependent induction of long-term synaptic plasticity at excitatory Golgi cell synapses of cerebellum

The Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage-dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca2+ channels, while LTD required uniquely activation of L-type Ca2+ channels. Notably, the voltage-dependence of plasticity at the mossy fiber-Golgi cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target cell. In aggregate, this result shows that Golgi cells show cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer. Significance statementThis paper shows for the first time a novel form of Ca2+ channel-dependent synaptic plasticity at the excitatory synapses impinging on cerebellar Golgi cells. This plasticity is bidirectional and inverted with respect to NMDA receptor-dependent paradigms, with LTD and LTP being favored at depolarized and hyperpolarized potentials, respectively. Furthermore, LTP and LTD induction requires differential involvement of T-ype and L-type voltage-gated Ca2+ channels rather than the NMDA receptors alone. These results, along with recent computational predictions, support the idea that Golgi cell plasticity could play a crucial role in controlling information flow through the granular layer along with cerebellar learning and memory.

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bioRxiv2019

Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ ATPase.

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca2+/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein (GFAP)-expressing astrocytes (astroglial calcineurin knock-out, ACN-KO). Here we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after-hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K+ homeostasis. Indeed, blockade of Na+/K+-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca2+-sensitive switch.

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bioRxiv2019

Parameter tuning differentiates granule cell subtypes enriching the repertoire of retransmission properties at the cerebellum input stage

The cerebellar granule cells (GrCs) form an anatomically homogeneous neuronal population which, in its canonical description, discharges regularly without adaptation. We show here that GrCs in fact generate diverse response patterns to current injection and synaptic activation, ranging from adaptation to acceleration of firing. Adaptation was predicted by parameter optimization in detailed GrC computational models based on the available knowledge on GrC ionic channels. The models also predicted that acceleration required the involvement of additional mechanisms. We found that yet unrecognized TRPM4 currents in accelerating GrCs could specifically account for firing acceleration. Moreover, adapting GrCs were better in transmitting high-frequency mossy fiber (MF) bursts over a background discharge than accelerating GrCs. This implied that different electroresponsive patterns corresponded to specific synaptic properties reflecting different neurotransmitter release probability. The correspondence of pre- and post-synaptic properties generated effective MF-GrC transmission channels, which could enrich the processing of input spike patterns and enhance spatio-temporal recoding at the cerebellar input stage.

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bioRxiv2019

Reconstruction and Simulation of a Scaffold Model of the Cerebellar Network

Reconstructing neuronal microcircuits through computational models is fundamental to simulate local neuronal dynamics. Here a scaffold model of the cerebellum has been developed in order to flexibly place neurons in space, connect them synaptically and endow neurons and synapses with biologically-grounded mechanisms. The scaffold model can keep neuronal morphology separated from network connectivity, which can in turn be obtained from convergence/divergence ratios and axonal/dendritic field 3D geometries. We first tested the scaffold on the cerebellar microcircuit, which presents a challenging 3D organization, at the same time providing appropriate datasets to validate emerging network behaviors. The scaffold was designed to integrate the cerebellar cortex with deep cerebellar nuclei (DCN), including different neuronal types: Golgi cells, granule cells, Purkinje cells, stellate cells, basket cells and DCN principal cells. Mossy fiber (mf) inputs were conveyed through the glomeruli. An anisotropic volume (0.077 mm3) of mouse cerebellum was reconstructed, in which point-neuron models were tuned toward the specific discharge properties of neurons and were connected by exponentially decaying excitatory and inhibitory synapses. Simulations using pyNEST and pyNEURON showed the emergence of organized spatio-temporal patterns of neuronal activity similar to those revealed experimentally in response to background noise and burst stimulation of mossy fiber bundles. Different configurations of granular and molecular layer connectivity consistently modified neuronal activation patterns, revealing the importance of structural constraints for cerebellar network functioning. The scaffold provided thus an effective workflow accounting for the complex architecture of the cerebellar network. In principle, the scaffold can incorporate cellular mechanisms at multiple levels of detail and be tuned to test different structural and functional hypotheses. A future implementation using detailed 3D multi-compartment neuron models and dynamic synapses will be needed to investigate the impact of single neuron properties on network computation.

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bioRxiv2018

Complex dynamics in simplified neuronal models: reproducing Golgi cell electroresponsiveness

Brain neurons exhibit complex electroresponsive properties - including intrinsic subthreshold oscillations and pacemaking, resonance and phase-reset - which are thought to play a critical role in controlling neural network dynamics. Although these properties emerge from detailed representations of molecular-level mechanisms in \"realistic\" models, they cannot usually be generated by simplified neuronal models (although these may show spike-frequency adaptation and bursting). We report here that this whole set of properties can be generated by the extended generalized leaky integrate-and-fire (E-GLIF) neuron model. E-GLIF derives from the GLIF model family and is therefore mono-compartmental, keeps the limited computational load typical of a linear low-dimensional system, admits analytical solutions and can be tuned through gradient-descent algorithms. Importantly, E-GLIF is designed to maintain a correspondence between model parameters and neuronal membrane mechanisms through a minimum set of equations. In order to test its potential, E-GLIF was used to model a specific neuron showing rich and complex electroresponsiveness, the cerebellar Golgi cell, and was validated against experimental electrophysiological data recorded from Golgi cells in acute cerebellar slices. During simulations, E-GLIF was activated by stimulus patterns, including current steps and synaptic inputs, identical to those used for the experiments. The results demonstrate that E-GLIF can reproduce the whole set of complex neuronal dynamics typical of these neurons - including intensity-frequency curves, spike-frequency adaptation, depolarization-induced and post-inhibitory rebound bursting, spontaneous subthreshold oscillations, resonance and phase-reset, - providing a new effective tool to investigate brain dynamics in large-scale simulations.

neuroscience↗

bioRxiv2018

Challenges and perspectives of functional sodium imaging (fNaI)

Brain function has been investigated via the blood oxygenation level dependent (BOLD) effect using magnetic resonance imaging (MRI) for the past decades. Advances in sodium imaging offer the unique chance to access signal changes directly linked to sodium ions (23Na) flux across the cell membrane, which generates action potentials, hence signal transmission in the brain. During this process 23Na transiently accumulates in the intracellular space. Here we show that quantitative functional sodium imaging (fNaI) at 3T is potentially sensitive to 23Na concentration changes during finger tapping, which can be quantified in grey and white matter regions key to motor function. For the first time, we measured a 23Na concentration change of 0.54 mmol/l in the ipsilateral cerebellum, 0.46 mmol/l in the contralateral primary motor cortex, 0.27 mmol/l in the corpus callosum and -11 mmol/l in the ipsilateral primary motor cortex, suggesting that fNaI is sensitive to distributed functional alterations. Open issues persist on the role of the glymphatic system in maintaining 23Na homeostasis, the role of excitation and inhibition as well as volume distributions during neuronal activity. Hemodynamic and physiological signal recordings coupled to realistic models of tissue function will be critical to understand the mechanisms of such changes and contribute to meeting the overarching challenge of measuring neuronal activity in vivo.

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bioRxiv2018

Adaptation of Whisker Movements Requires Cerebellar Potentiation

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading the behavioral response. Neuronal and behavior changes did not occur in two cell-specific mouse models with impaired long-term potentiation at parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.\n\nImpact statementRomano et al. show that expression of cerebellar whisker learning can be mediated by increases in simple spike activity, depending on LTP induction at parallel fiber to Purkinje cell synapses.

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