Grant: Discovery Grants Program - Individual

Brain cells typically communicate with each other at tiny and highly specialized regions known as synapses. At most of the synapses in our brains, the neurotransmitter glutamate is released from one neuron where it can induce a response in a neighboring neuron. That response is highly dependent on the glutamate receptors that are present in the area, how far the glutamate signal spreads, and how long glutamate remains at concentrations high enough to activate the receptors. For our brains to work efficiently, this glutamate signal must be very tightly regulated, and specialized proteins called transporters are required to soak up the released glutamate and recycle it for future use. Allowing too much glutamate to spill outside our synapses can create too much noise and negatively impact the ability for our brain cells to communicate with each other. Similarly, too much uptake by transporters can limit the availability of glutamate to act on its receptors, thereby weakening brain cell communication. In our NSE-funded program, we seek to better understand how the brain maintains tight control over the levels and spread of glutamate - its most abundant neurotransmitter - after it is released. We employ state-of-the-art imaging techniques using fluorescent markers that allow us to visualize synapses and transporters, and we use a glutamate sensor that allows us to watch glutamate actions in mouse brain tissue in real-time, and at the spatial resolution of individual synapses. Our preliminary observations demonstrate that individual synapses differ dramatically in the way they regulate glutamate; some clear it extremely fast while others take their time getting rid of the glutamate signal. We hypothesize that this heterogeneity of glutamate regulation at the individual synapse level is not random, but rather well-organized in a region-dependent and synapse-specific manner. In our short-term objectives, we first aim to better understand how the brain organizes its connections and transporter proteins to regulate glutamate levels at individual synapses (Aim 1). We then turn our attention to brain activity, and how different patterns of brain activity can cause long-term alterations to our synaptic structure and the interactions between transporters and individual synapses (Aim 2). Lastly, we will explore how the location of a particular type of transporter protein can play a critical role in recycling glutamate back to neurons for future use (Aim 3). Overall, our NSE program aims to unravel some of the mysteries of the seemingly random nature of the minute, nanoscopic details of our brain's connections, and how these differences impact the way our brain cells communicate with each other. We use numerous imaging techniques that vary in complexity, making our program a perfect training ground for HQP of all experience levels.