Glutamate homeostasis

Neurotransmitter transporters, like ion channels, play essential roles at synapses in the central nervous system as the major regulators of glutamate homeostasis. Glutamate homeostasis has been found to be important in the physiology of normal synapses, synaptic plasticity, neurodegenerative disease, demyelinating disorders, drug addiction, pain, and mental illness. We are studying the regulation of expression of glutamate transporters and the mechanisms linking their function to neuronal activity. This work has involved cloning of novel forms of glutamate transporters, identifying and characterizing protein interactors, investigating mechanisms of signal transduction that regulate transporter activity. Recently, we have generated a conditional knockout of the major glutamate transporter in the brain, GLT-1/EAAT2, to understand the distinct cell-type specific functions of GLT-1 expressed in neurons versus astrocytes. A major accomplishment of the lab has been the discovery that GLT-1, long thought to be exclusively a glial transporter, is the major glutamate transporter in excitatory terminals. Using conditional GLT-1 knockout mouse lines in which GLT-1 is deleted in astrocytes or in neurons, we have found that GLT-1 mediates a large amount of synaptosomal glutamate uptake, which is surprising, given that GLT-1 expressed in neurons is only a small fraction of total GLT-1 protein. Furthermore, in behavioral and biochemical phenotyping of the neuronal GLT-1 knockout mouse, we have found evidence that neuronal GLT-1 plays a critical role in the regulation of dopamine signaling. These finding are likely to be very important in our understanding of the basic mechanisms underlying drug addiction as well as mental illness, in particular, schizophrenia.

Mechanisms of oligodendrocyte (OL) injury

We study periventricular leukomalacia (PVL), the principal pathological lesion underlying cerebral palsy in premature infants. The primary cell-type injured in this lesion is the OL. For this reason, it is important to understand the mechanisms of death that kill OLs that might be activated in PVL. We have discovered that developing OLs are more vulnerable than mature OLs to both oxidative and excitotoxic injury. We are characterizing the mechanisms of cell death, the basis for the developmental regulation of the vulnerability to injury, as well as possible approaches for therapeutic intervention. These studies currently are focused on the role of Trp channels in oligodendrocyte development and differentiation.

Zinc as a regulator of survival and axon regeneration in the central nervous system

Using an optic nerve injury model, with Larry Benowitz we have discovered that free ionic zinc accumulates in the retina shortly after optic nerve injury. Further, we have found that preventing this accumulation by injecting chelators into the eye, or knocking out a specific zinc transporter, results in increased survival of retinal ganglion cells and, most remarkably, axon regeneration. We are currently studying the pathways by which zinc regulates both survival and regeneration.