The past year has seen a number of accomplishments. Several studies in patients with schizophrenia have been completed. First, in medication-free inpatients with schizophrenia we have shown that a genetic alteration in the BDNF gene, which affects release of brain-derived neurothrophin factor in the brain, impacts hippocampal function differentially in patients off antipsychotic medication compared to controls. Specifically, in patients, the Met allele was associated with decreased hippocampal regional cerebral blood flow (rCBF) whereas in healthy individuals, this genetic alteration was associated with increased hippocampal rCBF. Next, recognizing that the human brain is a complex biological system composed of many interacting subsystems with widespread functional networks that operate on a millisecond timescale we used magnetoencephalography (MEG) to identify functional networks of the so-called resting human brain in health and schizophrenia using two graphical tools, small worldness and degree distribution. The goal of this study was to determine whether functionally connected brain networks show non-random features in healthy controls and/or patients with schizophrenia on antipsychotics. Results showed that functional brain networks presented small world topologies and non-random degree distributions in both controls and patients with schizophrenia on antipsychotics. Additionally, we sought to understand how alterations in brain dopamine in schizophrenia and Parkinsons disease (PD) affect learning. Because (1) both types of patients share dysfunctions of dopaminergic neurotransmission, (2) previous studies of probabilistic association learning (PAL) in patients with schizophrenia on treatment with antipsychotics provided conflicting evidence for normal or abnormal probabilistic learning, and (3)studies of patients with Parkinson's receiving dopamine-augmenting drugs similarly report conflicting evidence for early PAL that elicits frontal-striatal activity, we examined the effects of dopamine-altering drugs on PAL. Patients with schizophrenia were studied before and after withdrawal from antipsychotic dopamine blockers, and PD patients were studied following treatment with dopamine-augmenting agents. We found that both blockade of dopamine receptors with antipsychotics in schizophrenia and the depletion of presynaptic dopamine that causes PD resulted in impairments of PAL. However, when dopamine receptor signaling was enhanced by removing the dopamine blocker in schizophrenia (but not by restoring the dopamine signal by replacement with dopamine augmenters in PD), some aspects of probabilistic association learning improved. We also explored the administration of tolcapone, an agent that inhibits catechol-O-methyltransferase (COMT), an enzyme that breaks down dopamine, because dopamine dysregulation is a core biological feature of schizophrenia, and because the gene that codes for COMT harbors a common variation that has been associated with schizophrenia risk and is implicated in both prefrontal and limbic functioning. Individuals who possess the high activity enzyme and have less DA in the frontal cortex have previously been found to perform worse than individuals who possess the low activity enzyme on tests of attention, concentration and memory and tolcapone effects on cognition are modulated by this variation. We have now explored the effect of tolcapone on cortical information processing during attention in healthy volunteers, hypothesizing that the drug would enhance efficiency of information processing in the prefrontal cortex. This randomized, double-blind, placebo-controlled, crossover study showed that tolcapone selectively improves the efficiency of information processing in the cortex of healthy volunteers. Our continued search for genes that affect cortical function and increase risk for developing schizophrenia led to the discovery of a variant of a potassium channel gene, KCNH2, that produces a form of the potassium channel that is specifically present in the brain, in contrast to a similar family of potassium channels present in the heart that interact with antipsychotics and can be associated with changes in the heart rhythm. The gene that produces this form of the potassium channel confers risk for schizophrenia and is highly expressed in the brains of patients. We examined drug-response data from two groups of patients: (1) those from the NIMH inpatient program in which patients are studied both while off medications for four weeks and while on antipsychotics for four weeks, and (2) those from the long-term, outpatient antipsychotic treatment (CATIE) study. In both groups of patients, antipsychotic treatment produced a significant improvement in symptoms, but patients who had the TT type of the KCHNH2 gene preferentially showed this response. Patients with this genotype were also the least likely to discontinue their antipsychotic treatment. This study may open new avenues for the development of new therapeutic strategies. Our work translating human genetic markers that are associated with risk for neuropsychiatric disorders into genetic mouse models has also produced several important advances. For example, in Carr (Behav Brain Res 2013) a mouse model lacking the DTNBP1 gene had learning and memory deficits from changes in PFC circuitry;they required more practice trials to reach a criterion. To study the effects of mutations in the risk gene, COMT, on brain functions, our group developed a knock-in mutant mouse carrying the human form of the gene. The mutant mice showed higher level of anxiety, which suggests that COMT is a genetic factor for emotional control. Since COMT mutation mainly affects the dopamine level in the prefrontal cortex, prefrontal dopamine might play an important role in anxiety. Additionally, since some cognitive functions differ in males and females Papaleo et al (PNAS 2012) tested in mice the interaction of these COMT mutations and sex, on environmental manipulations of cognitive functions such as attention, impulsivity, compulsivity, motivation, and rule-reversal learning. This work demonstrated a series of complex sex- and COMT-related effects and their interactions with environmental factors to influence specific executive cognitive domains. For example, changes in mild stress negatively affected cognitive performance in males, particularly those without the COMT gene, but not females. In contrast amphetamine treatment produced small sex-COMT genotype and sex-treatment interactions for compulsive behavior. Interestingly, females improved performance after repeated testing, worked harder and outperformed males. Since this mouse model mimics the human genotype, studies such as these may be useful for genotype-specific testing of medications such as COMT inhibitors for treatment of brain disorders including Parkinsons disease and schizophrenia.

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Gothelf, Doron; Law, Amanda J; Frisch, Amos et al. (2014) Biological effects of COMT haplotypes and psychosis risk in 22q11.2 deletion syndrome. Biol Psychiatry 75:406-13
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