Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.

GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.

Enuresis as a premorbid developmental marker of schizophrenia.

There is comparatively little information about premorbid maturational brain abnormalities in schizophrenia (SCZ). We investigated whether a history of childhood enuresis, a well-established marker of neurodevelopmental delay, is associated with SCZ and with measures of brain abnormalities also associated with SCZ. A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) based history of enuresis, volumetric brain MRI scans and neuropsychological testing were obtained in patients with SCZ, their non-psychotic siblings (SIB) and non-psychiatric controls (NC). The subjects were 211 patients (79.6% male), 234 of their SIB (43.2% male) and 355 controls (39.2% male). Frequency of enuresis was compared across groups and correlated with cognitive measures. Total and regional brain volumes were determined using voxel-based morphometry on matched subsets of probands (n = 82) with or without enuresis (n = 16, n = 66, respectively) and controls (n = 102) with or without enuresis (n = 11, n = 91, respectively). Patients with SCZ had higher rates of childhood enuresis (21%) compared with SIB (11%; chi(2) = 6.42, P = 0.01) or controls (7%; chi(2) = 23.65, P < 0.0001) and relative risk for enuresis was increased in SIB (lambda(S) = 2.62). Patients with enuresis performed worse on two frontal lobe cognitive tests [Letter Fluency (t = 1.97, P = 0.05, df = 200) and Category Fluency (t = 2.15, P = 0.03, df = 200)] as compared with non-enuretic patients. Voxel-based morphometry analysis revealed grey matter volume reductions in several frontal regions (right BA 9, right BA 10 and bilateral BA 45) and right superior parietal cortex (BA 7) in patients with a history of enuresis as compared with non-enuretic patients (all t > 3.57, all P < 0.001). The high frequency of childhood enuresis associated with SCZ and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a premorbid marker for neurodevelopmental abnormalities related to SCZ. These findings add to the evidence implicating prefrontal dysmaturation in this disorder, potentially related to genetic risk factors.

Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: critical examination of confounds.

Although previous studies report cognitive improvement following atypical antipsychotic administration in schizophrenia (SC), few placebo-controlled within-subject studies with examination of confounds (symptom reduction, cooperation, learning, and outliers) have been reported. The present study examines the effects of atypicals and confounds upon cognition in SC. The hypothesis tested was that relative to placebo, atypicals as a general class of medication would elicit cognitive improvement in SC. In all, 19 patients with SC (15 males) completed the double-blind, counterbalanced, randomized within-subject study of the effects of atypical antipsychotics (risperidone, clozapine, olanzapine, or quetiapine) vs placebo administration upon cognitive performance in the domains of executive function, attention, memory, language, visual perception, and general intellect. Significant cognitive improvement during atypical antipsychotic administration relative to placebo withdrawal occurred in most cognitive domains with robust improvements in intelligence (p=0.001), memory (p=0.0009), and fluency (p <0.002) even after outliers and unmotivated performances were excluded. These findings suggest that relative to placebo withdrawal, atypicals improve cognitive performance in SC. However, this finding may not be specific to atypicals, since analogous studies of typicals have not been performed.

Perceptual Category Judgment Deficits are Related to Prefrontal Decision Making Abnormalities in Schizophrenia.

Previous studies of perceptual category learning in patients with schizophrenia generally demonstrate impaired perceptual category learning; however, traditional cognitive studies have often failed to address the relationship of different cortical regions to perceptually based category learning and judgments in healthy participants and patients with schizophrenia. In the present study, perceptual category learning was examined in 26 patients with schizophrenia and 25 healthy participants using a dot-pattern category learning task. In the training phase, distortions of a prototypical dot pattern were presented. In the test phase, participants were shown the prototype, low and high distortions of the prototype, and random dot patterns. Participants were required to indicate whether the presented dot pattern was a member of the category of dot-patterns previously presented during the study phase. Patients with schizophrenia displayed an impaired ability to make judgments regarding marginal members of novel, perceptually based categories relative to healthy participants. Category judgment also showed opposite patterns of strong, significant correlations with behavioral measures of prefrontal cortex function in patients relative to healthy participants. These results suggest that impaired judgments regarding novel, perceptually based category membership may be due to abnormal prefrontal cortex function in patients with schizophrenia.

Dopaminergic therapy removal differentially effects learning in schizophrenia and Parkinson's disease.

Studies of patients with Parkinson's disease receiving dopamimetics report conflicting evidence for early learning of probabilistic cue-outcome associations that elicits frontal-striatal activity. Previous studies of probabilistic association learning in patients with schizophrenia administered antipsychotics have displayed conflicting evidence for normal and abnormal learning. The role of dopaminergic treatment (dopamimetic versus dopamine antagonistic) effects on probabilistic association learning in these diseases that directly impact the dopamine system is not fully understood. The current study examined the effects of dopaminergic therapies on probabilistic association learning in 13 patients with schizophrenia and 8 patients with Parkinson's disease under two conditions: after withdrawal from dopaminergic treatment and following administration of appropriate dopaminergic treatment. Medication order was counterbalanced in both groups. Patients with Parkinson's disease failed to demonstrate any significant improvement over 150 trials, under both conditions (receiving or withdrawn from dopamimetics). Patients with schizophrenia withdrawn from antipsychotics displayed significant improvement during later trials only. These results demonstrate an effect of dopamine (DA) signaling on probabilistic association learning in that: (1) dopamine replacement therapy in Parkinson's disease is insufficient to significantly improve probabilistic association learning and (2) DA receptor blockade impairs and removal of DA receptor blockade significantly improves frontal-striatal-dependent probabilistic association learning in schizophrenia, which is a novel finding and is opposite to the effects shown following removal of DA receptor blockade on other cognitive domains reported previously.

Habit and skill learning in schizophrenia: evidence of normal striatal processing with abnormal cortical input.

Different forms of nondeclarative learning involve regionally specific striatal circuits. The motor circuit (involving the putamen) has been associated with motor-skill learning and the dorsolateral prefrontal cortex (DLPFC) circuit (involving the caudate) has been associated with cognitive-habit learning. Efforts to differentiate functional striatal circuits within patient samples have been limited. Previous studies have provided mixed results regarding striatal-dependent nondeclarative learning deficits in patients with schizophrenia. In this study, a cognitive-habit learning task (probabilistic weather prediction) was used to assess the DLPFC circuit and a motor-skill learning task (pursuit rotor) was used to assess the motor circuit in 35 patients with schizophrenia and 35 normal controls. Patients with schizophrenia displayed significant performance differences from controls on both nondeclarative tasks; however, cognitive-habit learning rate in patients did not differ from controls. There were performance and learning-rate differences on the motor-skill learning task between the whole sample of patients and controls, however, analysis of a subset of patients and controls matched on general intellectual level eliminated learning rate differences between groups. The abnormal performance offset between patients with schizophrenia and controls in the absence of learning rate differences suggests that abnormal cortical processing provides altered input to normal striatal circuitry.