In the central nervous system, neuronal activity is a critical regulator of development and plasticity. Activity-dependent proliferation of healthy glial progenitors, oligodendrocyte precursor cells (OPCs), and the consequent generation of new oligodendrocytes contributes to adaptive myelination. This plasticity of myelin tunes neural circuit function and contributes to healthy cognition. The robust mitogenic effect of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, suggests that dysregulated or “hijacked” mechanisms of myelin plasticity might similarly promote malignant cell proliferation in this devastating group of brain cancers. Indeed, neuronal activity promotes progression of both high-grade and low-grade glioma subtypes in preclinical models. Crucial mechanisms mediating activity-regulated glioma growth include paracrine secretion of BDNF and the synaptic protein neuroligin-3 (NLGN3). NLGN3 induces multiple oncogenic signaling pathways in the cancer cell, and also promotes glutamatergic synapse formation between neurons and glioma cells. Glioma cells integrate into neural circuits synaptically through neuron-to-glioma synapses, and electrically through potassium-evoked currents that are amplified through gap-junctional coupling between tumor cells This synaptic and electrical integration of glioma into neural circuits is central to tumor progression in preclinical models. Thus, neuron-glial interactions not only modulate neural circuit structure and function in the healthy brain, but paracrine and synaptic neuron-glioma interactions also play important roles in the pathogenesis of glial cancers. The mechanistic parallels between normal and malignant neuron-glial interactions underscores the extent to which mechanisms of neurodevelopment and plasticity are subverted by malignant gliomas, and the importance of understanding the neuroscience of cancer.

Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know little about the importance of white matter abnormalities in epilepsy-associated co-morbidities. Epilepsy surgery is an important therapy strategy in patients where conventional anti-epileptic drug treatment fails . On histology of the resected brain samples, malformations of cortical development (MCD) are common among the epilepsy surgery population, especially focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). Both pathologies are associated with constitutive activation of the mTOR pathway. Interestingly, some type of FCD is morphological similar to TSC cortical tubers including the abnormalities of the white matter. Hypomyelination with lack of myelin-producing cells, the oligodendrocytes, within the lesional area is a striking phenomenon. Impairment of the complex myelination process can have a major impact on brain function. In the worst case leading to distorted or interrupted neurotransmissions. It is still unclear whether the observed myelin pathology in epilepsy surgical specimens is primarily related to the underlying malformation process or is just a secondary phenomenon of recurrent epileptic seizures creating a toxic micro-environment which hampers myelin formation. Interestingly, mTORC1 has been implicated as key signal for myelination, thus, promoting the maturation of oligodendrocytes . These results, however, remain controversial. Regardless of the underlying pathophysiologic mechanism, alterations of myelin dynamics, depending on their severity, are known to be linked to various kinds of developmental disorders or neuropsychiatric manifestations.

Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know little about the importance of white matter abnormalities in epilepsy-associated co-morbidities. Epilepsy surgery is an important therapy strategy in patients where conventional anti-epileptic drug treatment fails . On histology of the resected brain samples, malformations of cortical development (MCD) are common among the epilepsy surgery population, especially focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). Both pathologies are associated with constitutive activation of the mTOR pathway. Interestingly, some type of FCD is morphological similar to TSC cortical tubers including the abnormalities of the white matter. Hypomyelination with lack of myelin-producing cells, the oligodendrocytes, within the lesional area is a striking phenomenon. Impairment of the complex myelination process can have a major impact on brain function. In the worst case leading to distorted or interrupted neurotransmissions. It is still unclear whether the observed myelin pathology in epilepsy surgical specimens is primarily related to the underlying malformation process or is just a secondary phenomenon of recurrent epileptic seizures creating a toxic micro-environment which hampers myelin formation. Interestingly, mTORC1 has been implicated as key signal for myelination, thus, promoting the maturation of oligodendrocytes . These results, however, remain controversial. Regardless of the underlying pathophysiologic mechanism, alterations of myelin dynamics, depending on their severity, are known to be linked to various kinds of developmental disorders or neuropsychiatric manifestations.

Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and remyelination, and their cross talk to other cells, in particular oligodendrocytes and the progenitor cells. In addition, we are exploring the link between lipid metabolism and inflammation, and its role in the regulation of regeneration. I will report about our recent progress in our understanding of how microglia promote regeneration in the CNS.

Kaylene Young (Australia) – How does protocadherin 15 direct oligodendrocyte progenitor cell behaviour? Ben Emery (USA) - Loss of oligodendroglial support induces DLK-mediated degeneration of neurons; Carlie Cullen (Australia) – Do myelinating oligodendrocytes help us learn?

The gradual accumulation of hyperphosphorylated forms of the Tau protein (pTau) in the human brain correlate with cognitive dysfunction and neurodegeneration. I will present our recent findings on the consequences of human pTau aggregation in the hippocampal formation of a mouse tauopathy model. We show that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to their neurodegeneration. In aged but not younger mice, pTau spreads to oligodendrocytes. During ‘goal-directed’ navigation, we detect fewer high-firing pyramidal cells, but coupling to network oscillations is maintained in the remaining cells. The firing patterns of individually recorded and labelled pyramidal and GABAergic neurons are similar in transgenic and non-transgenic mice, as are network oscillations, suggesting intact neuronal coordination. This is consistent with a lack of pTau in subcortical brain areas that provide rhythmic input to the cortex. Spatial memory tests reveal a reduction in short-term familiarity of spatial cues but unimpaired spatial working and reference memory. These results suggest that preserved subcortical network mechanisms compensate for the widespread pTau aggregation in the hippocampal formation. I will also briefly discuss ideas on the subcortical origins of spatial memory and the concept of the cortex as a monitoring device.

The CNS is responsive to an ever-changing environment. Until recently, studies of neural plasticity focused almost exclusively on functional and structural changes of neuronal synapses. In recent years, myelin plasticity has emerged as a potential modulator of neural networks. Myelination of previously unmyelinated axons, and changes in the structure on already-myelinated axons, can have large effects on network function. The heterogeneity of the extent of how axons in the CNS are myelinated offers diverse scope for dynamic myelin changes to fine-tune neural circuits. The traditionally held view of myelin as a passive insulator of axons is now changing to one of lifelong changes in myelin, modulated by neuronal activity and experience. Myelin, produced by oligodendrocytes (OLs), is essential for normal brain function, as it provides fast signal transmission, promotes synchronization of neuronal signals and helps to maintain neuronal function. OLs differentiate from oligodendrocyte precursor cells (OPCs), which are distributed throughout the adult brain, and myelination continues into late adulthood. OPCs can sense neuronal activity as they receive synaptic inputs from neurons and express voltage-gated ion channels and neurotransmitter receptors, and differentiate into myelinating OLs in response to changes in neuronal activity. This lecture will explore to what extent myelin plasticity occurs in adult animals, whether myelin changes occur in non-motor learning tasks, especially in learning and memory, and questions whether myelin plasticity and myelin regeneration are two sides of the same coin.

The amyloid cascade hypothesis for Alzheimer disease ((Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Selkoe, 1991), updated in (Karran et al., 2011) provides a linear model for the pathogenesis of AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggregation or Aβ oligomer formation could not be convincingly demonstrated until now. Indeed, many questions (e.g. what causes Aβ toxicity, what is the relation between Aβ and Tau pathology, what causes neuronal death, why is amyloid deposition not correlated with dementia etc…) were already raised when the amyloid hypothesis was conceived 25 years ago. These questions remain in essence unanswered. It seems that the old paradigm is not tenable: the amyloid cascade is too linear, too neurocentric, and does not take into account the long time lag between the biochemical phase i.e. the appearance of amyloid plaques and neuronal tangles and the ultimate clinical phase, i.e. the manifestation of dementia. The pathways linking these two phases must be complex and tortuous. We have called this the cellular phase of AD (De Strooper and Karran, 2016) to suggest that a long period of action and reaction involving neurons, neuronal circuitry but also microglia, astroglia, oligodendrocytes, and the vasculature underlies the disease. In fact it is this long disease process that should be studied in the coming years. While microglia are part of this process, they should not be considered as the only component of the cellular phase. We expect that further clinical investigations and novel tools will allow to diagnose the effects of the cellular changes in the brain and provide clinical signs for this so called preclinical or prodromal AD. Furthermore the better understanding of this phase will lead to completely novel drug targets and treatments and will lead to an era where patients will receive an appropriate therapy according to their clinical stage. In this view anti-amyloid therapy is probably only effective and useful in the very early stage of the disease and AD does no longer equal to dementia. We will discuss in our talk how single cell technology and transplantation of human iPS cells into mouse brain allow to start to map in a systematic way the cellular phase of Alzheimer’s Disease.