Background and PurposeInsufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D1 receptor‐dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D1 receptor function.Experimental ApproachCognitive performance of the D1 receptor agonist, SKF38393, was studied in the T‐maze continuous alternation task and 5‐choice serial reaction time task. D1 receptor/PDE1B double‐immunohistochemistry was performed using human and rat prefrontal brain sections. The pharmacological activity of the PDE1 inhibitor, ITI‐214, was assessed by measuring the increase in cAMP/cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on the modulation of prefrontal neuronal transmission by SKF38393 and ITI‐214 were performed using extracellular recordings in brain slices.Key ResultsSKF38393 improved working memory and attentional performance in rodents. D1 receptor/PDE1B co‐expression was verified in both human and rat prefrontal brain sections. The pharmacological activity of ITI‐214 on its target, PDE1, was demonstrated by its ability to increase prefrontal cAMP/cGMP. In addition, ITI‐214 improved working memory performance. Both SKF38393 and ITI‐214 facilitated neuronal transmission in prefrontal brain slices.Conclusion and ImplicationsWe hypothesize that PDE1 inhibition improves working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data, therefore, support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction.

SUMMARY The effects of the visual features of prey-like objects on the orienting behaviour of the salamander Plethodon jordani were studied. Two stimuli (cricket dummies, rectangles), moving in opposite directions, were presented simultaneously on a computer screen. They differed in size, contrast, velocity and movement pattern of the entire body or the body appendages. Size and velocity appeared to be the dominant features; shape was of lesser importance. Contrast and movement pattern were of intermediate importance and local motion of little importance. This rank order was the same when the probability of a response to the different stimuli was estimated by means of the maximum-likelihood method. Cluster analysis revealed that in all animals stimuli could be grouped into five clusters. Among individuals, the rank order of stimuli was similar for high- and low-ranking stimuli and varied for those of intermediate rank; stimuli could be grouped into 3–5 clusters. Our findings favour the view that, in amphibians, prey recognition is guided by a number of visual features acting either alone or in combination and depending on internal motivational or attentional states and individual experience. Movie available on-line: http://www.biologists.com/JEB/movies/jeb3864.html.

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Background Schizophrenia is a complex neurodevelopmental disorder. Patients typically start exhibiting symptoms during adolescence, coinciding with a critical period for the maturation of the prefrontal cortex. While previous studies have identified deficits in cortical interneuron integrity and network function in chronic patients, little is known about the maladaptive circuitry in the early prodromal phase of the disease. To assess pathophysiological changes during adolescence that might contribute to the disruption of cortical network function we have studied a 15q13.3 microdeletion mouse model Df[h15q13]−/+ resembling a human copy number variant (CNV) known to confer high risk for psychiatric disorders such as schizophrenia. Using a combination of histology, in vitro electrophysiology and electroencephalography (EEG) we explored the interneuronal connectivity and cortical network functionality in the Df[h15q13]−/+ mouse model from adolescence to early adulthood Methods Immunohistological analysis was performed on brain slices within the prefrontal cortex, dorsal hippocampus and amygdala region from Df[h15q13]−/+ and wild-type mice (N=8) at PND35 and PND70 (4 sections/brain). Sections were immunostained for markers of interneuron subtypes and respective synapses. Fluorescence images were recorded and processed with an Opera Phenix (PerkinElmer) using the 63x objective in confocal mode. EEG studies were performed on Df[h15q13]−/+ and wild-type mice within the age range of PND41 to PND70 (6). Mice were obtained from Taconic and housed within the experimental facility for at least one week prior to experimental procedures. Results We initially confirmed that the adult Df[h15q13]−/+ microdeletion mouse model exhibits robust markers reminiscent of schizophrenia-linked pathology, such as the reduction of parvalbumin positive (PV+) interneurons, lower abundance of perineuronal net proteins (PNNs) and an impaired cortical processing of sensory information. We identified abnormalities in the number and distribution of interneuron synapses in the prefrontal cortex, hippocampus and amygdala, the phenotype in the adolescent brain, which were opposed to pathophysiological changes identified in adult Df[h15q13]−/+ microdeletion mice. We discovered an enhanced inhibitory drive from specific subpopulations of interneurons during adolescence that might contribute to deficits in the adult hippocampal and PFC network. Likewise, we found Df[h15q13]−/+ specific differences in cortical network processing between adolescent and adult mice revealed by EEG. To align the development of cortical network function to the progressive changes in network structure we performed longitudinal EEG recordings and uncovered particular abnormalities in basal and evoked oscillatory rhythms in adolescent and adult mice. Discussion In this study, we discovered abnormalities in the interneuron integration during a critical period for the maturation of the prefrontal cortex in a 15q13.3 microdeletion mouse model. Our findings provide novel insights into early deficits in the limbic and cortical neuronal networks that may drive circuit dysfunction in schizophrenia patients. Identification of adolescent pathophysiology in models for schizophrenia risk will provide the opportunity to explore new mechanisms for early intervention.