Date of Award
Doctor of Philosophy (PhD)
Baker, David A.
Schizophrenia is a debilitating disorder involving impaired cognition, disorganized thinking, and auditory hallucinations that has a tremendous unmet medical need, potentially because current antipsychotics insufficiently target the pathophysiology of the disease. The neural basis of schizophrenia appears to involve abnormal activity within the dorsolateral prefrontal cortex (PFC) in which efferent neurons exhibit disorganized firing patterns. Synchronization of cortical activity is regulated by complex inter-neuronal connections, which is compromised in schizophrenia. Schizophrenic’s exhibit reduced PFC volume that may reflect reduced arborization leading to diminished inter-neuronal connectivity. An unexplored explanation is that reduced volume reflects changes in astrocytes, cells positioned to control synchronized firing at up to 100K synapses. Glutamate release, including from system xc - which exchanges one intracellular glutamate for an extracellular cystine, is emerging as a component of astrocytic neuronal regulation and is altered in the PFC of schizophrenics. To determine the importance of system xc - dysregulation, we examined the impact of increased or decreased activity to glutamate levels in the PFC and PFC mediated behaviors that are used to model schizophrenia.
Decreased system xc - activity, achieved using the inhibitor sulfasalazine (SSZ), produced a phenotype that mirrored aspects of schizophrenia and reduced extracellular glutamate levels in the PFC. Specifically, SSZ produced deficits in sensorimotor gating, cognition, and anxiety – all of which involve the PFC and are altered in schizophrenia. Similar to schizophrenia, system xc - dysregulation was detected, and appears to be central to the cognitive deficits in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia.
Increased system xc - activity, achieved using the cysteine prodrug Nacetylcysteine, reversed multiple behavioral deficits present in preclinical models of schizophrenia. Namely, N-acetylcysteine reversed sensorimotor gating deficits produced by phencyclidine, an acute model of schizophrenia, and reversal learning deficits in the MAM model. Notably, chronic N-acetylcysteine attenuated behavioral deficits and normalized aspects of system xc - activity in MAM-treated rats.
Collectively, these data position system xc - as a key regulator of behavioral output from the prefrontal cortex and indicate that system xc - dysregulation in schizophrenia may be an important component of the pathology of the disease. In addition, increased system xc - may represent an effective therapeutic endpoint.