Nervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) that supply presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is largely unknown. I will discuss our recent advances in our understanding of how key components of the presynaptic machinery for neurotransmitter release are transported and assembled focussing on our studies in genome-engineered human induced pluripotent stem cell-derived neurons. Specifically, I will focus on the composition and cell biological identity of the axonal transport vesicles that shuttle key components of neurotransmission to nascent synapses and on machinery for axonal transport and its control by signaling lipids. Our studies identify a crucial mechanism mediating the delivery of SV and active zone proteins to developing synapses and reveal connections to neurological disorders. In the second part of my talk, I will discuss how exocytosis and endocytosis are coupled to maintain presynaptic membrane homeostasis. I will present unpublished data regarding the role of membrane tension in the coupling of exocytosis and endocytosis at synapses. We have identified an endocytic BAR domain protein that is capable of sensing alterations in membrane tension caused by the exocytotic fusion of SVs to initiate compensatory endocytosis to restore plasma membrane area. Interference with this mechanism results in defects in the coupling of presynaptic exocytosis and SV recycling at human synapses.

Early in development the nervous system is constructed with far too many neurons that make an excessive number of synaptic connections.  Later, a wave of neuronal remodeling radically reshapes nervous system wiring and cell numbers through the selective elimination of excess synapses, axons and dendrites, and even whole neurons.  This remodeling is widespread across the nervous system, extensive in terms of how much individual brain regions can change (e.g. in some cases 50% of neurons integrated into a brain circuit are eliminated), and thought to be essential for optimizing nervous system function.  Perturbations of neuronal remodeling are thought to underlie devastating neurodevelopmental disorders including autism spectrum disorder, schizophrenia, and epilepsy.  This seminar will discuss our efforts to use the relatively simple nervous system of Drosophila to understand the mechanistic basis by which cells, or parts of cells, are specified for removal and eliminated from the nervous system.

The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. We have recently established that the activity of voltage-gated Ca++ channels is crucial for the adequate migration, proliferation and maturation of oligodendrocyte progenitor cells (OPCs). Furthermore, we have found that voltage-gated Ca++ channels that function in synaptic communication between neurons also mediate synaptic signaling between neurons and OPCs. Thus, we hypothesize that voltage-gated Ca++ channels are central components of OPC-neuronal synapses and are the principal ion channels mediating activity-dependent myelination.

Neurons and neural circuits can produce stereotyped and reliable output activity on the basis of highly variable cellular, synaptic, and circuit properties. This is crucial for proper nervous system function throughout an animal’s life in the face of growth, perturbations, and molecular turnover. But how can reliable output arise from neurons and synapses whose parameter vary between individuals in a population, and within an individual over time? I will review how a combination of experimental and computational methods can be used to examine how neuron and network function depends on the underlying parameters, such as neuronal membrane conductances and synaptic strengths. Within the high-dimensional parameter space of a neural system, the subset of parameter combinations that produce biologically functional neuron or circuit activity is captured by the notion of a ‘solution space’. I will describe solution space structures determined from electrophysiology data, ion channel expression levels across populations of neurons and animals, and computational parameter space explorations. A key finding centers on experimental and computational evidence for parameter correlations that give structure to solution spaces. Computational modeling suggests that such parameter correlations can be beneficial for constraining neuron and circuit properties to functional regimes, while experimental results indicate that neural circuits may have evolved to implement some of these beneficial parameter correlations at the cellular level. Finally, I will review modeling work and experiments that seek to illuminate how neural systems can homeostatically navigate their parameter spaces to stably remain within their solution space and reliably produce functional output, or to return to their solution space after perturbations that temporarily disrupt proper neuron or network function.

What happens when the nervous system fails to adapt? Our perception of the world relies on a nervous system that learns and adapts to sensory information. Based on our experience we can predict what a wooden surface will feel like, that fire is hot, and that a gentle caress from a partner can be soothing. But our sensory experience of the world is not static – warm water can feel like fire on sunburned skin and the gentle brush of our clothes can be excruciating after an injury. In pathological conditions such as chronic pain, changes in nervous system function can cause normally innocuous sensory stimuli to be perceived as aversive or painful long after the initial injury has happened. These changes can sometimes be similar to the formation of a pain ‘memory’ that can modulate and distort our perception of sensory information. Our research program seeks to understand how fundamental processes that govern the formation and maintenance of plastic changes in the nervous system can lead to pathological conditions and how we can reverse engineer these changes to treat chronic conditions.

We are interested in understanding how microbes impact the behavior of host animals. Animal nervous systems likely evolved in environments richly surrounded by microbes, yet the impact of bacteria on nervous system function has been relatively under-studied. A challenge has been to identify systems in which both host and microbe are amenable to genetic manipulation, and which enable high-throughput behavioral screening in response to defined and naturalistic conditions. To accomplish these goals, we use an animal host — the roundworm C. elegans, which feeds on bacteria — in combination with its natural gut microbiome to identify inter-organismal signals driving host-microbe interactions and decision-making. C. elegans has some of the most extensive molecular, neurobiological and genetic tools of any multicellular eukaryote, and, coupled with the ease of gnotobiotic culture in these worms, represents a highly attractive system in which to study microbial influence on host behavior. Using this system, we discovered that commensal bacterial metabolites directly modulate nervous system function of their host. Beneficial gut microbes of the genus Providencia produce the neuromodulator tyramine in the C. elegans intestine. Using a combination of behavioral analysis, neurogenetics, metabolomics and bacterial genetics we established that bacterially produced tyramine is converted to octopamine in C. elegans, which acts directly in sensory neurons to reduce odor aversion and increase sensory preference for Providencia. We think that this type of sensory modulation may increase association of C. elegans with these microbes, increasing availability of this nutrient-rich food source for the worm and its progeny, while facilitating dispersal of the bacteria.