Mismatch Negativity And Theta Band Oscillation In Schizophrenia And Rodent Nmdar Models

s | 35 schizophrenia. High fat, very low carbohydrate ketogenic diet (KD) induces adaptive changes in brain energy metabolism through bypassing impaired metabolic pathways and increasing energy reserves. We hypothesised that KD may have beneficial effects in schizophrenia. To test this hypothesis we studied the effects of KD in NMDA receptor hypofunction models of schizophrenia by measuring a variety of behavioural abnormalities reflecting positive, negative and cognitive aspects of schizophrenia. METHODS: Acute NMDA receptor hypofunction was induced by a single injection of different doses of the non-competitive NMDA receptor antagonist dizocilpine (MK-801). For the chronic NMDA hypofunction model MK-801 (1 mg/kg) was administered daily for 4 weeks. Mice were fed with either standard mouse diet or KD (77.6, 9.5, 9.4 % and 30.8 MJ/kg fat, protein and carbohydrate content and digestible energy, respectively) for 3 and 7 weeks. Schizophrenia-like behaviours such as psychomotor hyperactivity, increased stereotyped behaviour, impaired sensorimotor gating; social interaction deficits and impaired working memory were measured following acute or chronic MK-801 administration. RESULTS: KD effectively normalised the entire spectrum of schizophrenia-like behaviours, including psychomotor hyperactivity, stereotyped behaviour, impaired social interaction, spatial working memory deficits and impaired PPI induced by acute MK-801 administration. KD also normalised social interaction deficits induced by chronic (4 weeks) MK-801 administration. Furthermore, KD resulted in decreased body weight gain and lowering of blood glucose levels. Our analysis also confirmed that the beneficial behavioural effects of KD are independent of temporarily decreased calorie intake or body weight loss. CONCLUSIONS: These results raise the possibility that KD might be effectively used to normalise schizophrenia-related behaviours. The beneficial metabolic effects suggest that KD may also help to mitigate metabolic abnormalities during antipsychotic treatment. PM369 Shift in ErbB4 Splicing is Associated with Developmental Pruning of Excitatory Synapses on Parvalbumin Interneurons in Monkey Prefrontal Cortex Daniel W. Chung, Kenneth N. Fish, David A. Lewis Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA Abstract Background: In experimental systems, loss of ErbB4 signaling results in deficient excitatory drive to parvalbumin (PV) interneurons and schizophrenia-like phenotypes. Thus, the pathogenesis of schizophrenia may involve excessive pruning of excitatory inputs to PV interneurons. We tested the hypothesis that developmental pruning occurs at excitatory synapses on PV interneurons and is associated with changes in ErbB4 expression in monkey dorsolateral prefrontal cortex (DLPFC). Methods: We quantified mRNA levels of PV, ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2) and Pan-ErbB4 in DLPFC layer 4 (where PV interneurons are enriched) from 42 macaque monkeys ranging in age from postnatal 1 week to 132 months. From a subset of these monkeys, sections were labeled using antibodies for PV, VGlut1 and PSD95 and the density of VGlut1+/PSD95+ puncta per PV+ cell bodies was calculated. Results: From 3 to 40 months, Pan-ErbB4 expression remained stable, ErbB4 JM-a to JM-b variants ratio increased by 92%, the density of VGlut+/PSD95+ puncta onto PV+ neurons decreased by 19%, and VGlut1 and PSD95 levels within VGlut+/PSD95+ puncta onto PV+ neurons increased by 26% and 34%, respectively. The ratio of ErbB4 JM-a to JM-b variants was negatively correlated with the density of VGlut1+/PSD95+ puncta onto PV+ neurons. Conclusions: These findings suggest that a developmental shift in ErbB4 splicing is associated with pruning of excitatory synapses on PV interneuron. As ErbB4 splicing is dysregulated in schizophrenia, our findings suggest that over-pruning of excitatory synapses on PV interneurons could contribute to PV interneuron dysfunction in schizophrenia.Background: In experimental systems, loss of ErbB4 signaling results in deficient excitatory drive to parvalbumin (PV) interneurons and schizophrenia-like phenotypes. Thus, the pathogenesis of schizophrenia may involve excessive pruning of excitatory inputs to PV interneurons. We tested the hypothesis that developmental pruning occurs at excitatory synapses on PV interneurons and is associated with changes in ErbB4 expression in monkey dorsolateral prefrontal cortex (DLPFC). Methods: We quantified mRNA levels of PV, ErbB4 splicing variants (JM-a, JM-b, CYT-1, CYT-2) and Pan-ErbB4 in DLPFC layer 4 (where PV interneurons are enriched) from 42 macaque monkeys ranging in age from postnatal 1 week to 132 months. From a subset of these monkeys, sections were labeled using antibodies for PV, VGlut1 and PSD95 and the density of VGlut1+/PSD95+ puncta per PV+ cell bodies was calculated. Results: From 3 to 40 months, Pan-ErbB4 expression remained stable, ErbB4 JM-a to JM-b variants ratio increased by 92%, the density of VGlut+/PSD95+ puncta onto PV+ neurons decreased by 19%, and VGlut1 and PSD95 levels within VGlut+/PSD95+ puncta onto PV+ neurons increased by 26% and 34%, respectively. The ratio of ErbB4 JM-a to JM-b variants was negatively correlated with the density of VGlut1+/PSD95+ puncta onto PV+ neurons. Conclusions: These findings suggest that a developmental shift in ErbB4 splicing is associated with pruning of excitatory synapses on PV interneuron. As ErbB4 splicing is dysregulated in schizophrenia, our findings suggest that over-pruning of excitatory synapses on PV interneurons could contribute to PV interneuron dysfunction in schizophrenia. PM370 Mismatch negativity and theta band oscillation in schizophrenia and rodent NMDAR models Migyung Lee1, Andrea Balla2, Daniel C Javitt1 1Columbia University College of Physicians and Surgeons, USA, 2Nathan Kline Institute, USA Abstract Objective: Mismatch negativity (MMN) is a reliable biomarker of N-methyl-D-aspartate receptor (NMDAR) dysfunction in schizophrenia. The present study investigates effects of the NMDAR antagonist PCP in rodents on MMN-related event-related spectral perturbation (ERSP) patterns, vs. deficit patterns observed in schizophrenia. Method: Rats (n=21) were implanted with skull electrodes over frontal, parietal and bilateral auditory cortex. MMN was obtained to both frequency and duration (10% each) against a background of more frequency standards. PCP (15 mg/kg/d) was administered by osmotic minipump with or without simultaneous oral glycine treatment. EEG was collected from control (n=7), PCP (n=8) and PCP+glycine (n=6) groups, at baseline, 2-week, and 4-week time points. In parallel clinical MMN was collected from schizophrenia (n=69) and control (n=38) subjects using a similar paradigm. Results: Rodent MMN varied significantly across groups (F(1,18)=12.5 p<.001), with significant reduction by PCP (p<.001 vs. control) and restoration by glycine (p<.001 vs. PCP alone). In ITC analysis, MMN was associated with increased activity in theta and gamma frequencies that were reduced by PCP treatment. Simultaneous, glycine treatment increased activity within gamma frequency bands vs. PCP alone(F(1,12)=4.6 p<.05). In humans, MMN deficits were associated with both reduced ITC and ERSP of theta frequency response to deviant stimuli (F(1,105)=62.2 p<.001; F(1,105)=15.2 p<.001) and reduced alpha frequency response to standards (t=3.8 p<.00; t=3.2 p<.00), similar to the pattern of deficit observed in the rodent PCP model and reversed by glycine treatment(F(1,12)=6.1 p<.05). Conclusion: These findings demonstrate first that deficits in MMN generation correspond primarily to reductions in theta frequency activity in humans consistent with prior reports [1], and second that rodent chronic PCP treatment may serve as an appropriate animal model for schizophrenia treatment development. Glycine treatment partially reversed ERSP induced by PCP treatment, suggesting sensitivity to NMDAR agonist intervention.Objective: Mismatch negativity (MMN) is a reliable biomarker of N-methyl-D-aspartate receptor (NMDAR) dysfunction in schizophrenia. The present study investigates effects of the NMDAR antagonist PCP in rodents on MMN-related event-related spectral perturbation (ERSP) patterns, vs. deficit patterns observed in schizophrenia. Method: Rats (n=21) were implanted with skull electrodes over frontal, parietal and bilateral auditory cortex. MMN was obtained to both frequency and duration (10% each) against a background of more frequency standards. PCP (15 mg/kg/d) was administered by osmotic minipump with or without simultaneous oral glycine treatment. EEG was collected from control (n=7), PCP (n=8) and PCP+glycine (n=6) groups, at baseline, 2-week, and 4-week time points. In parallel clinical MMN was collected from schizophrenia (n=69) and control (n=38) subjects using a similar paradigm. Results: Rodent MMN varied significantly across groups (F(1,18)=12.5 p<.001), with significant reduction by PCP (p<.001 vs. control) and restoration by glycine (p<.001 vs. PCP alone). In ITC analysis, MMN was associated with increased activity in theta and gamma frequencies that were reduced by PCP treatment. Simultaneous, glycine treatment increased activity within gamma frequency bands vs. PCP alone(F(1,12)=4.6 p<.05). In humans, MMN deficits were associated with both reduced ITC and ERSP of theta frequency response to deviant stimuli (F(1,105)=62.2 p<.001; F(1,105)=15.2 p<.001) and reduced alpha frequency response to standards (t=3.8 p<.00; t=3.2 p<.00), similar to the pattern of deficit observed in the rodent PCP model and reversed by glycine treatment(F(1,12)=6.1 p<.05). Conclusion: These findings demonstrate first that deficits in MMN generation correspond primarily to reductions in theta frequency activity in humans consistent with prior reports [1], and second that rodent chronic PCP treatment may serve as an appropriate animal model for schizophrenia tre