The Multifaceted Role of Glutamate at Excitatory and Inhibitory Synapses

Our thoughts, memories, and actions are finely controlled by the coordinated activity of neural circuits in the brain. Prior work has identified a multitude of molecular mechanisms that contribute to the generation of these higher order functions, yet we know very little about how our ability to learn and perform habitual actions change depending on how far neurotransmitters released from neurons can travel away from their point of release. This is the main focus of my work, which I carried out using a diverse toolbox and focusing on two brain regions: the hippocampus and the striatum. The hippocampus controls learning and memory. The striatum controls the execution of learnt motor programs. There are four main outcomes of this work, each of which is described in full details in an original publication. First, I identified that glutamate escape from the synaptic cleft varies at different times of the day, due to changes in astrocyte morphology, and activates different populations of receptors, due to changes in their expression level on the plasma membrane. These effects are triggered by corticosterone, a hormone that is released into the bloodstream in varying amounts at different times of the day. Second, I found that in vitro recording conditions that mimic more closely the composition of the cerebrospinal fluid, with specific reference to calcium ions, alter spillover mediated activation of a class of metabotropic glutamate receptors called mGluRIII. This results in changes in the spatial representation of the external environment in CA1 place cells. Third, neuronal glutamate transporters alter glutamate spillover and mGluRI expression in the striatum. Fourth, I found that the expression of this transporter at synapses formed between specific classes of striatal neurons is important to limit multitasking in mice. Taken together, these findings shed light on the importance of understanding the functional properties of synapses in vitro and in vivo to understand the operating principles of neuronal circuits. More importantly, they show how crucial it is to preserve their function to prevent the onset of cognitive and neuropsychiatric disease.