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Plenary Lectures
Monday 18th
Opening Words
"EDUARDO DE ROBERTIS"
LECTURE
An old drug for new treatment: neuroprotective effects of doxycycline in Parkinson Disease
Rita Raisman-Vozari
Parkinson’s disease (PD) is a neurodegenerative disorder for which only symptomatic treatments, such as levodopa and dopamine agonists are available. These drugs ameliorate motor symptoms however they could induce adverse side effects. The mechanism that drives the chronic progression of PD remains elusive. Among the proposed underlying pathophysiological mechanisms, aggregation of α-synuclein, neuroinflammation, and oxidative stress, have been credited to contribute to neuronal loss. Thus, to efficiently modify the course of neurodegeneration in PD, an ideal drug should be capable of interfering with α-synuclein aggregation, halting the generation of toxic species, and inhibiting neuroinflammatory processes. Doxycycline (DOX), a wide-spectrum antibiotic that belongs to the group of the tetracyclines has been suggested by our international research team for repurposing in PD, due to the fact that it has anti-inflammatory and antioxidant properties and mitigates the loss of dopaminergic neurons in an animal model of PD. In addition, we showed that DOX inhibit the pathological aggregation of α-synuclein by reshaping toxic oligomeric species towards strains with reduced toxicity, seeding capacity, and propensity to form amyloid fibril and attenuates the production of mitochondrial-derived reactive oxygen species. During my talk, I will provide strong evidence that doxycycline treatment may be an effective strategy against PD and other synucleinopathies.
Tuesday 19th
Plenary Lecture:
Signals from the 4th Dimension Regulate Drug Relapse
Peter Kalivas
Treatments for psychiatric disorders, such as substance use and stress disorders, are based on ameliorating behavioral symptoms, not reversing drug- and stress-induced synaptic pathology that has the potential to cure disorders. This failing arises in part from a research focus limited to understanding how pre and postsynaptic physiology is changed when in fact key neuropathology exists in the perisynaptic neuropil that homeostatically regulates synaptic transmission. I will review recent preclinical findings from our lab and others using animal models of substance use and stress disorder that point to a key role by perisynaptic astroglia and signaling in the extracellular matrix (ECM) in regulating stress- and drug-induced synaptic pathology. These data reveal that drug and stress insults initiate long-lasting changes in brain synapses via enduring neuroadaptations in astroglia and the ECM. Moreover, conditioned cue-induced drug seeking and stress responses arise from transient post-synaptic plasticity that is orchestrated by equally transient morphological changes in perisynaptic astroglia and ECM signaling. I will conclude the presentation with a discussion on how to further understand and therapeutically employ extrasynaptic regulators in treating substance use and stress disorders.
Plenary Lecture:
What is "optimal" brain development? It depends on a child's environment
Silvia Bunge
There has been an explosion of research on human brain development over the past 20 years. As a result, we have learned a lot about the features of brain anatomy and brain function that change over childhood and adolescence and that help to explain individual differences in cognition, affect, and behavior. However, the vast majority of brain imaging study samples skew towards middle- or higher-income individuals; we know next to nothing about how the brain develops in children living in poverty. Here, I describe a pattern of brain communication that has been shown in a number of studies to be associated with better cognitive performance – and then show how this finding does not generalize to children living below the poverty line. This work serves as a reminder that biological features that are adaptive for one population may not be for another.
Wednesday 20th
Plenary Lecture:
An in vitro model to study the early pathophysiology of amyotrophic lateral sclerosis
Andrea Nistri
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting motoneurons with ensuing paralysis and fatal outcome. There is currently no cure for this condition which belongs to the class of diseases caused by intracellular protein misfolding whose origin remains obscure. Elucidating this process remains difficult because ALS is often diagnosed with delay, thus preventing recognition and ideally treatment of the disease at its earliest stage. One important cause of motoneuron distress that might trigger a cascade of cellular events leading to late neurodegeneration is excessive buildup of extracellular glutamate, the main excitatory neurotransmitter at the level of motoneurons. These cells would therefore become overexcited and suffer from “excitotoxicity” with subsequent neuronal death. Our lab has developed a new model of motoneuron excitotoxicity by pharmacological block of the glutamate clearance system in the rat brainstem and observed with patch clamping and calcium imaging the gradual onset of group bursting whereby motoneuron clusters (recruited via gap junctions) generate strong rhythmic discharges that slowly evolve to neuronal death. We have shown that pharmacological approaches to depress excitation by enhancing inhibition or blocking excitatory currents prevent the generation of this deadly rhythmic activity and rescue motoneurons from degeneration, suggesting a potential early target to combat the development of ALS.
Plenary Lecture:
Of Synapses and Domesticated Viruses
Vivian Budnik
The functional role of “junk DNA” in the organism, and in particular the nervous system, is largely unknown. However, new evidence suggests that a master regulator of synaptic plasticity, activity-regulated cytoskeleton-associated protein (Arc) is a domesticated transposable element (TE) that serves as a mechanism to transport RNAs across the synapse. In this mechanism, the ViSyToR (Viral Synaptic Transfer of RNA) pathway, Arc protein forms viral-like capsids that package arc RNA. These capsids are loaded into extracellular vesicles that travel across synaptic partners to provide a signal for new synapse formation. New unpublished evidence suggests that another TE, Copia, thought to belong to the junk DNA has a physiological function at synapses that antagonizes the action of Arc. These studies lend further support to recent arguments and data suggesting that TEs and potentially other types of junk DNA are not junk after all.
Thursday 21th
Plenary Lecture:
Lipid dynamics in synaptic plasticity: lessons from Niemann Pick diseases
María Dolores Ledesma
Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie the synaptic plasticity required for memory, learning and emotional processes. Efforts have been made to characterize the protein machinery controlling spine dynamics but we know much less about the involvement of lipids despite being major membrane components. Sphingomyelin and cholesterol are particularly enriched in synapses. Imbalance in the levels of these lipids lead to cognitive and psychiatric alterations as in Niemann Pick diseases. In the talk I will present evidence obtained in mouse models for these disorders supporting a relevant role for sphingomyelin and cholesterol in synaptic plasticity by influencing actin dynamics, calcium homeostasis and neurotransmitter receptor physiology. We will also present data on how these lipids are regulated at spines, on the pathological consequences of their alterations and on strategies to counteract these consequences that open therapeutic perspectives for the currently fatal Niemann Pick diseases.
Plenary Lecture:
Striatins in peripheral nerve development
M. Laura Feltri
During development, Schwann cells undergo extensive cytoskeletal reorganization as they insert cytoplasmic extensions into axon bundles to sort, ensheath, and myelinate axons. This process is regulated by Rac1. Our lab previously demonstrated that Rac1 activation during development is driven by engagement of alpha6beta1 integrin with laminins, and that this is essential for radial sorting. Additionally, we showed that the co-transcriptional activatosr YAP and TAZ, downstream of the Hippo pathway, are also essential for Schwann cell development and control alpha6beta1 integrin expression. Here we performed a proteomic screen to identify novel Rac1 effectors in peripheral nerves and identified striatin-3 (Strn3) as a candidate. In vitro and in vivo data indicate that striatins are essential for Schwann cell development and myelination, probably by connecting Rac1 to the inhibition of the Hippo pathway.
Friday 22th
"Ranwell Caputto" Lecture:
Steady changes in the composition of the neuronal plasma membrane are an early event of the brain aging phenotype
Carlos Dotti
Aging comes with a panoply of changes in genomic and non-genomic activities ( i.e. mitochondrial dysfunction, altered intracellular trafficking, proteostasis defects, calcium dyshomeostasis, etc.). Is there a “master” mechanism upstream of all (or some) of these defects? A change that satisfies this condition is hormonal signalling: it is altered with age, it occurs in all cells of our organs and tissues, and influences genomic and non-genomic activities. Hormonal systems that change with age and contribute to the functional decline typical of old age are the thyroid hormone system, sex hormones, the growth hormone superfamily, and the insulin-like growth factor (IGF) superfamily. In addition to these hormones, glucocorticoids, mainly cortisol must also be considered. While some of the defects in hormone signalling with age may be due to an intrinsic mechanism of age (sex hormones), in others the defect is not in hormone levels but in their ability to induce an effect upon binding to their cognate receptors. This type of defect is known as hormone signal resistance. Therefore, the question to ask now is what is hormone resistance with age (in the central nervous system we must add resistance to neurotransmitter signalling) due to?. In my talk I will present data that suggest that small but persistent changes in the lipid composition of the plasma membrane with age cause the loss of signaling power of (different) membrane receptors, and how these changes occur.