As you read this, information is being received by specialized endings of your sensory cells, and transmitted through a web of ~quadrillion synapses (specialized contact sites where two neuron-endings communicate) made by ~100 billion neurons in your brain, and back to instruct your hand to move the cursor.
Throughout animal life, our nervous system is constantly at work, allowing us to engage with the world around us. It achieves this remarkable feat through the concerted effort of its two fundamental cell types – neurons and glia. These two cell types exist in approximately equal numbers in our nervous systems, and are lineally related. Glia physically and molecularly interact closely with neurons and neuron-endings at each step of a neural circuit, and modulate their shape and activity to enable effective information relay (Figure 1). Proper molecular communications between glia and neurons are critical for every aspect of nervous system function. Not surprisingly, then, disrupted interactions between these two cells are implicated in many neurological disorders of development (e.g. Autism), function (sensory dysfunction and cognitive impairment) and aging (e.g. Alzheimer’s).
Understanding how glia and neurons communicate with each other is essential, if we are to decipher how our brains make sense of the world, store memories and execute meaningful behaviors; and how disruption of this conversation leads to disease states. However, the functions of glia, or how they interact with neurons, are poorly defined at molecular resolution.
We aim to identify molecular mechanisms by which glia modulate neuron shape, function, neural circuit activity and animal behavior, in health and disease.
C. elegans is a powerful genetic system in which to investigate molecular and cellular mechanisms of glia-neuron interactions in vivo (Figure 2). Any of its 56 distinct glia or 302 neurons can be manipulated individually and reproducibly at single-gene resolution. Effects of these perturbations can be monitored across multiple levels, from molecular (genetic networks, genomics, transgenics, protein biochemistry), to cellular (cell shape and cell-cell contacts by conventional, super-resolution or electron microscopy; circuits (functional imaging of neural activity within its mapped connectome), and quantifiable animal behaviors.
We typically use all of these approaches to understand glia-neuron interactions; and will co-opt or develop additional methods, tools and techniques, as needed, to tackle a given scientific question.
We developed a single glia-neuron pair as our first model, and found that glia dynamically regulate the ionic micro-environment of the neuron-ending to modulate its shape and function throughout animal life (Figure 3). This in turn influences the animal’s sensory perception, associated memory of what it sensed, and consequent behavioral responses. Our identification of one of the molecular pathways underlying this process (Singhvi et al, 2016) suggests that this novel module may be a clinically relevant and broadly conserved mechanism by which glia modulate neurons.
In addition, our studies indicated that glia in fact use not one, but multiple, molecular pathways to regulate their associated neurons. We aim to identify each of these molecular pathways and mechanisms of glia-neuron communication, and understand how each of these is regulated under different contexts.
Each of the astrocyte glial cells in our brains associates with many neurons (estimated at tens of thousands) and each neuron interacts with different glia. Whether each glia-neuron contact is molecularly distinct and specific to each given pair of cells is a fundamental and open question in understanding the functional logic of our nervous system.
We recently found molecular evidence suggesting that glia-neuron interactions may be highly specific, and differently regulated, even within a single glial cell interacting with different neurons in C. elegans (Figure 4). Using these preliminary observations as a molecular genetic tool, we are investigating the functional specificity of glia-neuron contacts in the nervous system in molecular detail. We want to know how this specificity is established and regulated, and its implication for information processing and integration in the nervous system.
Many glia types engulf (prune) neuronal fragments. Astrocytes or microglia prune synapses and the retinal pigment epithelium (RPE) glia-like cells inside mammalian retina engulf the endings of photoreceptor neurons. Defects in these processes is correlated with many neurological diseases of development (e.g. Autism) and aging (e.g. Alzheimer’s), however molecular mechanisms underlying glial engulfment of neuronal fragments is not well understood.
We recently discovered that C. elegans glia also engulf neuronal-endings, similar to mammalian astrocytes pruning synapses. Our current research is focused on exploiting the powerful molecular genetic toolkit of C. elegans to understand how this process is executed and regulated.
Long term, we also envision exploiting insights from our studies in C. elegans to inform directed investigations of select pathways in other experimental systems and relevant disease models.