Innovation in Schizophrenia Therapeutics: A TAAR1-Centered Approach

Research Category: Health Sciences

Schizophrenia is a debilitating psychiatric disorder characterized by behavioral, cognitive, mood, and psychological impairments. Schizophrenic individuals experience a range of positive symptoms such as hallucinations and delusions, and negative symptoms such as apathy and anhedonia. Current treatment methods largely depend on pharmacologically blocking Dopamine D2 receptors, though about one-third of patients suffer severe side effects or experience a worsening of condition. Dysregulation in glutamate transmission is also implicated in the severity of schizophrenia and presents as a target in developing more effective therapeutics. Specifically, glutamate transporters are critical in maintaining the concentration of active glutamate in the cell synapse, which is dysregulated in schizophrenia. Here, we aim to determine whether a novel G-protein coupled receptor, Trace Amine Associated Receptor 1 (TAAR1), can modulate the activity of the glutamate transporters EAAT1 and EAAT2 in astrocytes, which are specialized glial cells that regulate extracellular glutamate in the brain. Both TAAR1 and glutamate transporters were found to be expressed in human astrocytes. We are now assessing whether TAAR1-specific ligands can regulate the localization of the EAAT1 and EAAT2 glutamate transporters on the extracellular membrane using immunofluorescence techniques. The ability of TAAR1-targeted drugs to regulate the membrane localization of glutamate transporters, thereby regulating the ability of astrocytes to clear extracellular glutamate, represents a potential new target in modulating glutamate transmission and the first step in creating a new class of schizophrenia treatments.