73 It is thus of particular interest that auditory evoked gamma-band activity is not only reduced in SCZ patients but also in first-degree relatives,74 as well as in unaffected, monozygotic twins,75 suggesting that high-frequency oscillations qualify as an endophenolype. Following this line of reasoning, several animal models have been examined for the effects of risk genes on E/I balance parameters

and changes in high-frequency oscillations. “Disrupted-In-Schizophrenia-1” (DISC1) Inhibitors,research,lifescience,medical is a gene whose chromosomal translocation is associated with an increased incidence of major mental disorders, including SCZ.76 Flikida and colleagues77 generated a transgenic mouse with a dominant-negative (DN) truncated DISCI and examined several anatomical parameters. DN-DISC1 mice were AZD4547 mw characterized by a selective reduction of PV immunoreactivity, PV being a Ca++-scavenger Inhibitors,research,lifescience,medical with preferential location in fast-spiking

GABAergic-neurons that play a major role in the generation of high frequency oscillations. Another SCZ-susceptibility gene, Neuregulin-1 (NRG I), has been shown to increase the power of gamma-band oscillations in hippocampal slices.78 This enhancement is mediated through the activation of ErbB4 receptors on PV interneurons. Finally, DTNBP1 is a gene that encodes the protein dystrobrevin-binding protein Inhibitors,research,lifescience,medical 1 (dysbindin-1) and has been found to be reduced in SCZ patients.79 Reduced dysbindin-1 Inhibitors,research,lifescience,medical expression in mice caused reduced phasic inhibition of PV cells which in turn was associated with impaired auditory evoked gamma-band activity.80

The relationship between genetic risk factors and long-range synchronization was examined in a study by Sigurdson et al.81 The authors measured the synchronization between the hippocampus and the prefrontal cortex during a working memory (WM) task in Df(16)Al/mice which provide a genetic model for the microdeletion on human chromosome 22 (22qll.2).The 22qll.2 microdeletion is one of the strongest genetic risk factors for SCZ.82 Df(16)A1/- mice were characterized byimpaired WM performance which was closely correlated with reduced phase-locking of Inhibitors,research,lifescience,medical theta-band oscillations between prefrontal and hippocampal cells, suggesting that the genetic risk Thymidine kinase for SCZ impacts directly on large-scale interactions which in turn could underlie the cognitive deficits associated with the disorder. Perspectives for high-frequency oscillations in schizophrenia The available evidence suggests that SCZ is associated with aberrant high-frequency oscillations which could potentially explain core features of the disorders, such as the pronounced impairments of cognitive functions. Importantly, available evidence also establishes close relations between alterations in E/I balance parameters and oscillatory activity. These novel data emphasize the close relations between genetics, signaling cascades — especially those involving inhibitory mechanisms and NMDA receptors — and abnormal brain dynamics.