Editorial for This Special Issue "Synaptic Transmission: From Molecular to Neural Network Levels".

We invited contributions reporting new evidence of synaptic mechanisms and their network-level impacts for this Special Issue [...

Anisotropy and Frequency Dependence of Signal Propagation in the Cerebellar Circuit Revealed by High-Density Multielectrode Array Recordings.

The cerebellum is one of the most connected structures of the central nervous system and receives inputs over an extended frequency range. Nevertheless, the frequency dependence of cerebellar cortical processing remains elusive. In this work, we characterized cerebellar cortex responsiveness to mossy fibers activation at different frequencies and reconstructed the spread of activity in the sagittal and coronal planes of acute mouse cerebellar slices using a high-throughput high-density multielectrode array (HD-MEA).

Dopaminergic Modulation of Prefrontal Cortex Inhibition.

The prefrontal cortex is the highest stage of integration in the mammalian brain. Its functions vary greatly, from working memory to decision-making, and are primarily related to higher cognitive functions. This explains the considerable effort devoted to investigating this area, revealing the complex molecular, cellular, and network organization, and the essential role of various regulatory controls.

Variations on the theme: focus on cerebellum and emotional processing.

The cerebellum operates exploiting a complex modular organization and a unified computational algorithm adapted to different behavioral contexts. Recent observations suggest that the cerebellum is involved not just in motor but also in emotional and cognitive processing. It is therefore critical to identify the specific regional connectivity and microcircuit properties of the emotional cerebellum.

Deconstruction of Neurotrypsin Reveals a Multi-factorially Regulated Activity Affecting Myotube Formation and Neuronal Excitability.

Neurotrypsin (NT) is a highly specific nervous system multi-domain serine protease best known for its selective processing of the potent synaptic organizer agrin. Its enzymatic activity is thought to influence processes of synaptic plasticity, with its deregulation causing accelerated neuromuscular junction (NMJ) degeneration or contributing to forms of mental retardation. These biological effects are likely to stem from NT-based regulation of agrin signaling.

The Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models.

Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders that include a variety of forms and clinical phenotypes. This heterogeneity complicates the clinical and experimental approaches to ASD etiology and pathophysiology. To date, a unifying theory of these diseases is still missing.

Non-Linear Frequency Dependence of Neurovascular Coupling in the Cerebellar Cortex Implies Vasodilation-Vasoconstriction Competition.

Neurovascular coupling (NVC) is the process associating local cerebral blood flow (CBF) to neuronal activity (NA). Although NVC provides the basis for the blood oxygen level dependent (BOLD) effect used in functional MRI (fMRI), the relationship between NVC and NA is still unclear. Since recent studies reported cerebellar non-linearities in BOLD signals during motor tasks execution, we investigated the NVC/NA relationship using a range of input frequencies in acute mouse cerebellar slices of vermis and hemisphere.

The Optogenetic Revolution in Cerebellar Investigations.

The cerebellum is most renowned for its role in sensorimotor control and coordination, but a growing number of anatomical and physiological studies are demonstrating its deep involvement in cognitive and emotional functions. Recently, the development and refinement of optogenetic techniques boosted research in the cerebellar field and, impressively, revolutionized the methodological approach and endowed the investigations with entirely new capabilities. This translated into a significant improvement in the data acquired for sensorimotor tests, allowing one to correlate single-cell activity with motor behavior to the extent of determining the role of single neuronal types and single connection pathways in controlling precise aspects of movement kinematics.

Diverse Neuron Properties and Complex Network Dynamics in the Cerebellar Cortical Inhibitory Circuit.

Neuronal inhibition can be defined as a spatiotemporal restriction or suppression of local microcircuit activity. The importance of inhibition relies in its fundamental role in shaping signal processing in single neurons and neuronal circuits. In this context, the activity of inhibitory interneurons proved the key to endow networks with complex computational and dynamic properties.

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 Ca /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-expressing astrocytes (astroglial calcineurin KO [ACN-KO]).

Corrigendum: Long-Lasting Response Changes in Deep Cerebellar Nuclei Correlate With Low-Frequency Oscillations.

[This corrects the article DOI: 10.3389/fncel.2019.

Long-Lasting Response Changes in Deep Cerebellar Nuclei Correlate With Low-Frequency Oscillations.

The deep cerebellar nuclei (DCN) have been suggested to play a critical role in sensorimotor learning and some forms of long-term synaptic plasticity observed have been proposed as a possible substrate. However, till now it was not clear whether and how DCN neuron responses manifest long-lasting changes . Here, we have characterized DCN unit responses to tactile stimulation of the facial area in anesthetized mice and evaluated the changes induced by theta-sensory stimulation (TSS), a 4 Hz stimulation pattern that is known to induce plasticity in the cerebellar cortex .

Hyperexcitability and Hyperplasticity Disrupt Cerebellar Signal Transfer in the KO Mouse Model of Autism.

Autism spectrum disorders (ASDs) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASDs has been suggested, but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 (Islet Brain-2) KO mice of either sex.

Neuronal Activity-Dependent Activation of Astroglial Calcineurin in Mouse Primary Hippocampal Cultures.

Astrocytes respond to neuronal activity by generating calcium signals which are implicated in the regulation of astroglial housekeeping functions and/or in modulation of synaptic transmission. We hypothesized that activity-induced calcium signals in astrocytes may activate calcineurin (CaN), a calcium/calmodulin-regulated protein phosphatase, implicated in neuropathology, but whose role in astroglial physiology remains unclear. We used a lentiviral vector expressing NFAT-EYFP (NY) fluorescent calcineurin sensor and a chemical protocol of LTP induction (cLTP) to show that, in mixed neuron-astrocytic hippocampal cultures, cLTP induced robust NY translocation into astrocyte nuclei and, hence, CaN activation.

Activation of the CREB/ Pathway during Long-Term Synaptic Plasticity in the Cerebellum Granular Layer.

The induction of long-term potentiation and depression (LTP and LTD) is thought to trigger gene expression and protein synthesis, leading to consolidation of synaptic and neuronal changes. However, while LTP and LTD have been proposed to play important roles for sensori-motor learning in the cerebellum granular layer, their association with these mechanisms remained unclear. Here, we have investigated phosphorylation of the cAMP-responsive element binding protein (CREB) and activation of the immediate early gene pathway following the induction of synaptic plasticity by theta-burst stimulation (TBS) in acute cerebellar slices.

Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System.

Unlabelled: Neurovascular coupling (NVC) is the process whereby neuronal activity controls blood vessel diameter. In the cerebellum, the molecular layer is regarded as the main NVC determinant. However, the granular layer is a region with variable metabolic demand caused by large activity fluctuations that shows a prominent expression of NMDA receptors (NMDARs) and nitric oxide synthase (NOS) and is therefore much more suitable for effective NVC.

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue.

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits.

Corrigendum: Integration and regulation of glomerular inhibition in the cerebellar granular layer circuit.

[This corrects the article on p. 55 in vol. 8, PMID: 24616663.

Corrigendum: Regulation of output spike patterns by phasic inhibition in cerebellar granule cells.

[This corrects the article on p. 246 in vol. 8, PMID: 25202237.

Distributed Circuit Plasticity: New Clues for the Cerebellar Mechanisms of Learning.

The cerebellum is involved in learning and memory of sensory motor skills. However, the way this process takes place in local microcircuits is still unclear. The initial proposal, casted into the Motor Learning Theory, suggested that learning had to occur at the parallel fiber-Purkinje cell synapse under supervision of climbing fibers.

Integrated plasticity at inhibitory and excitatory synapses in the cerebellar circuit.

The way long-term potentiation (LTP) and depression (LTD) are integrated within the different synapses of brain neuronal circuits is poorly understood. In order to progress beyond the identification of specific molecular mechanisms, a system in which multiple forms of plasticity can be correlated with large-scale neural processing is required. In this paper we take as an example the cerebellar network, in which extensive investigations have revealed LTP and LTD at several excitatory and inhibitory synapses.

Stim and Orai proteins in neuronal Ca(2+) signaling and excitability.

Stim1 and Orai1 are ubiquitous proteins that have long been known to mediate Ca(2+) release-activated Ca(2+) (CRAC) current (ICRAC) and store-operated Ca(2+) entry (SOCE) only in non-excitable cells. SOCE is activated following the depletion of the endogenous Ca(2+) stores, which are mainly located within the endoplasmic reticulum (ER), to replete the intracellular Ca(2+) reservoir and engage specific Ca(2+)-dependent processes, such as proliferation, migration, cytoskeletal remodeling, and gene expression. Their paralogs, Stim2, Orai2 and Orai3, support SOCE in heterologous expression systems, but their physiological role is still obscure.

The intellectual disability protein RAB39B selectively regulates GluA2 trafficking to determine synaptic AMPAR composition.

RAB39B is a member of the RAB family of small GTPases that controls intracellular vesicular trafficking in a compartment-specific manner. Mutations in the RAB39B gene cause intellectual disability comorbid with autism spectrum disorder and epilepsy, but the impact of RAB39B loss of function on synaptic activity is largely unexplained. Here we show that protein interacting with C-kinase 1 (PICK1) is a downstream effector of GTP-bound RAB39B and that RAB39B-PICK1 controls trafficking from the endoplasmic reticulum to the Golgi and, hence, surface expression of GluA2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs).