Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.

There is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. We asked whether Akt1 deficiency in mice results in structural and functional abnormalities in prefrontal cortex (PFC). Exploratory transcriptional profiling revealed concerted alterations in the expression of PFC genes controlling synaptic function, neuronal development, myelination, and actin polymerization, and follow-up ultrastructural analysis identified consistent changes in the dendritic architecture of pyramidal neurons. Behavioral analysis indicated that Akt1-mutant mice have normal acquisition of a PFC-dependent cognitive task but abnormal working memory retention under neurochemical challenge of three distinct neurotransmitter systems. Thus, Akt1 deficiency creates a context permissive for gene-gene and geneenvironment interactions that modulate PFC functioning and contribute to the disease risk associated with this locus, the severity of the clinical syndrome, or both. mouse model ͉ psychiatric disease ͉ susceptibility gene T here is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. This includes convergent evidence for a decrease in Akt1 protein levels and levels of substrate phosphorylation in brains of some individuals with schizophrenia (1, 2), a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine in an Akt1-deficient mouse model (1), as well as pharmacological evidence indicating that drugs used in the management of psychosis such as lithium, haloperidol and clozapine, can act as enhancers of AKT signaling in vivo (1, 3), or in vitro (4). Indeed, AKT is a key signaling intermediate downstream of dopamine receptor D2 (DRD2), the best-established target of antipsychotic drugs. AKT function is important for normal dopaminergic transmission and expression of dopamine-associated behaviors (5) in a manner distinct from, but perhaps cooperative to, cAMP͞DARPP32-dependent signaling, traditionally associated with the D1 class of receptors. An association between schizophrenia and AKT1 genetic variants has also been reported in three large family samples of European descent (1, 6, 7), but not in a family sample of Asian descent (8).A diverse and convergent body of data from both in vivo and postmortem approaches suggests that prefrontal cortex (PFC) is central to the pathophysiology of schizophrenia (9-14). Although studies of individuals with schizophrenia are, in principle, confounded by the effect of treatment and the course of the disease, more recent studies of animal models of leading candidate susceptibility genes (15, 16) that are free of such confounding influences, also reveal deficits in PFC functioning. Individuals with schizophrenia show varying degrees of deficiency in a diverse range of cognitive domains (17). In particular, deficits that are attributed primarily to PFC dysfunction, such as impaired working memory (18), are considered a cardinal cognitive symptom of schizophrenia (19). Previous work in animal models has sh...

In humans, anxiety disorders are often accompanied by an overactive autonomic nervous system, reflected in increased body temperature (BT) and heart rate (HR). In rodents, comparable effects are found after exposure to stress. These autonomic parameters can give important information on stress and anxiety responses in mice. In the present experiments, stress reactivity of three frequently used mouse strains [129 Sv/Ev, Swiss Webster (SW) and C57 BL/6] was assessed using their autonomic stress responses. BT, HR and activity were telemetrically measured. Undisturbed circadian rhythms already showed clear differences between the mouse strains. Hereafter, autonomic responses to stressors with increasing intensity were measured. Strain differences were found in magnitude and duration of the stress responses, especially after high-intensity stressors. Generally, C57BL/6 mice showed the largest autonomic response, SW the lowest and the 129Sv/Ev the intermediate response. Interestingly, the observed ranking in autonomic stress response does not match the behavioral stress responsivity of these strains. Finally, sensitivity to the anxiolytic diazepam (0, 1, 2, 4 and 8 mg/kg) was tested using the stress-induced hyperthermia paradigm. Pharmacological sensitivity to diazepam differed between the strains with the 129Sv/Ev being most sensitive. These studies show that simultaneous measurement of behavioral and autonomic parameters under stressful conditions contributes considerably to a better interpretation of anxiety and stress levels in mice.

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