Major depressive disorder (MDD) is associated with cortical abnormalities, including fewer glial cells (e.g. Ongur et al. 1998), dysregulated glutamatergic neurotransmission (Paul and Skolnick 2003), and elevated neuronal activity (Mayberg et al. 2005). Because glial cells play a key role in trafficking the excitatory neurotransmitter glutamate, it is likely that these pathologies are related. Recent reports suggest a causal link between glutamatergic function and the treatment of depression by demonstrating that ketamine, an antagonist at NMDA (glutamate) receptors, has antidepressant effects in humans and laboratory animals (Maeng et al. 2007;Zarate et al. 2006). In addition, very recent work suggests that glial ablation can produce depressive-like effects in animals (Banasr et al. 2008). Thus there is mounting evidence that glutamatergic transmission and glial cell function may play important roles in both the pathophysiology and relief of mood disorders. Based on these observations, I hypothesize that reduced glial glutamate trafficking can induce signs of depression. I will test this hypothesis using pharmacological manipulations that prevent glutamate trafficking by glial cells and two complimentary behavioral tests that index motivation, intracranial self-stimulation and place conditioning. Although MDD is made up of complex symptoms such as feelings of worthlessness and suicidal ideation, some aspects of the symptoms of depression can be modeled using these behavioral tests including diminished interest in pleasure (anhedonia) and depressed mood (dysphoria). Using these tools and microinjection techniques, I will determine if mood is regulated by glial glutamate transmission throughout the brain or restricted to the prefrontal cortex (PFC). These studies provide an animal model of abnormalities that are present in depressed humans and seek to determine whether they contribute to the etiology of depression. This is a novel approach that will broaden our understanding of the pathophysiological relevance of deficits that are associated with depression in humans in the regulation of mood in rodents, which has a high likelihood of facilitating the development of new more effective treatment strategies. PUBLIC HEALTH RELEVANCE: The proposed studies seek to enhance our understanding of the causes of major depression. This will be accomplished by exploring the relevance of glial cell deficits that are associated with depression in humans in the regulation of mood in rodents. This work has a high likelihood of facilitating the development of new more effective treatment strategies.