Synaptic health in Parkinson's Disease
Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1% of over 65's; there is currently no effective treatment. Dopaminergic neuronal loss is hallmark in PD and yet despite decades of intensive research there is still no known therapeutic which will completely halt the disorder. As a result, identification of interventive therapies to reverse or prevent PD are essential. Using genetically faithful models (induced pluripotent stem cells and knock-in mice) of familial late onset PD (LRRK2 G2019S and GBA N370S) we have contributed to the literature that neuronal dysfunction precedes degeneration. Specifically, using whole cell patch clamp electrophysiology, biochemical, behavioural and molecular biological techniques, we have begun to investigate the fundamental processes that make neurons specialised i.e., synaptic function and neurotransmission. We illustrate those alterations to spontaneous neurotransmitter release, neuronal firing, and short-term plasticity as well as Ca2+ and energy dyshomeostasis, are some of the earliest observable pathological dysfunctions and are likely precursors to late-stage degeneration. These pathologies represent targets which can be manipulated to address causation, rather than the symptoms of the PD, and represent a marker that, if measurable in patients, could form the basis of early PD detection and intervention.
Roles of microglia in the pathogenesis of neurodegeneration
Microglia are implicated in a variety of functions in the central nervous system, ranging from shaping neural circuits during early brain development, to surveying the brain parenchyma, and providing trophic support to neurons across the entire lifespan. In neurodegeneration, microglia have been considered for long time mere bystanders, accompanying and worsening neuronal damage. However, recent evidence indicates that microglia can causally contribute to neurodegenerative diseases, and that their dysfunction can even be at the origin of the pathology. In fact, the broad range of physiological roles microglia play in the healthy brain suggest that faulty microglia can initiate neurodegeneration through several possible mechanisms. In particular, in this seminar, we will discuss how dysfunctional microglia can affect synaptic function leading to pathological synapse loss, thus putting microglia center stage in the pathogenesis of brain disorders.
Memory, learning to learn, and control of cognitive representations
Biological neural networks can represent information in the collective action potential discharge of neurons, and store that information amongst the synaptic connections between the neurons that both comprise the network and govern its function. The strength and organization of synaptic connections adjust during learning, but many cognitive neural systems are multifunctional, making it unclear how continuous activity alternates between the transient and discrete cognitive functions like encoding current information and recollecting past information, without changing the connections amongst the neurons. This lecture will first summarize our investigations of the molecular and biochemical mechanisms that change synaptic function to persistently store spatial memory in the rodent hippocampus. I will then report on how entorhinal cortex-hippocampus circuit function changes during cognitive training that creates memory, as well as learning to learn in mice. I will then describe how the hippocampus system operates like a competitive winner-take-all network, that, based on the dominance of its current inputs, self organizes into either the encoding or recollection information processing modes. We find no evidence that distinct cells are dedicated to those two distinct functions, rather activation of the hippocampus information processing mode is controlled by a subset of dentate spike events within the network of learning-modified, entorhinal-hippocampus excitatory and inhibitory synapses.
Memory, learning to learn, and control of cognitive representations
Biological neural networks can represent information in the collective action potential discharge of neurons, and store that information amongst the synaptic connections between the neurons that both comprise the network and govern its function. The strength and organization of synaptic connections adjust during learning, but many cognitive neural systems are multifunctional, making it unclear how continuous activity alternates between the transient and discrete cognitive functions like encoding current information and recollecting past information, without changing the connections amongst the neurons. This lecture will first summarize our investigations of the molecular and biochemical mechanisms that change synaptic function to persistently store spatial memory in the rodent hippocampus. I will then report on how entorhinal cortex-hippocampus circuit function changes during cognitive training that creates memory, as well as learning to learn in mice. I will then describe how the hippocampus system operates like a competitive winner-take-all network, that, based on the dominance of its current inputs, self organizes into either the encoding or recollection information processing modes. We find no evidence that distinct cells are dedicated to those two distinct functions, rather activation of the hippocampus information processing mode is controlled by a subset of dentate spike events within the network of learning-modified, entorhinal-hippocampus excitatory and inhibitory synapses.
Presynaptic plasticity in hippocampal circuits
Christophe Mulle is a cellular neurobiologist with expertise in electrophysiology of synaptic transmission and an international leader in studies on glutamate receptors and hippocampal synaptic plasticity. He was among the first to identify and characterize functional nicotinic receptors in the mammalian brain while working in the laboratory of Jean-Pierre Changeux at the Pasteur Institute. He then generated knock-out mice for KAR subunits at the Salk Institute in the laboratory of Steve Heinemann, which have proven to be instrumental for understanding the function of these elusive glutamate receptors in synaptic function and plasticity.