Long-term memory is formed by alterations in glutamate-dependent excitatory synaptic transmission, which is in turn regulated by synaptosomal protein of 25 kDa (SNAP-25), a key component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex essential for exocytosis of neurotransmitter-filled synaptic vesicles. Both reduced and excessive SNAP-25 activity has been implicated in various disease states that involve cognitive dysfunctions such as attention deficit hyperactivity disorder, schizophrenia and Alzheimer's disease. Here, we over-express SNAP-25 in the adult rat dorsal hippocampus by infusion of a recombinant adeno-associated virus vector, to evaluate the consequence of late adolescent-adult dysfunction of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein in the absence of developmental disruption. We report a specific and significant increase in the levels of extracellular glutamate detectable by microdialysis and a reduction in paired-pulse facilitation in the hippocampus. In addition, SNAP-25 over-expression produced cognitive deficits, delaying acquisition of a spatial map in the water maze and impairing contextual fear conditioning, both tasks known to be dorsal hippocampal dependent. The high background transmission state and pre-synaptic dysfunction likely result in interference with requisite synapse selection during spatial and fear memory consolidation. Together these studies provide the first evidence that excess SNAP-25 activity, restricted to the adult period, is sufficient to mediate significant deficits in the memory formation process

J. Neurochem. (2010) 113, 601–614. Abstract The critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon‐associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.

Background: Liver stiffness measurements can be used to assess liver fibrosis and can be acquired by transient elastography using FibroScan® and with Acoustic Radiation Force Impulse imaging. The study aimed to establish liver stiffness measurement scores using FibroScan® and Acoustic Radiation Force Impulse in a chronic hepatitis C cohort and to explore the correlation and agreement between the scores and the factors influencing agreement. Methods: Patients had liver stiffness measurements acquired with FibroScan® (right lobe of liver) and Acoustic Radiation Force Impulse (right and left lobe of liver). We used Spearman’s correlation to explore the relationship between FibroScan® and Acoustic Radiation Force Impulse scores. A Bland–Altman plot was used to evaluate bias between the mean percentage differences of FibroScan® and Acoustic Radiation Force Impulse scores. Univariable and multivariable analyses were used to assess how factors such as body mass index, age and gender influenced the agreement between liver stiffness measurements. Results: Bland-Altman showed the average (95% CI) percentage difference between FibroScan® and Acoustic Radiation Force Impulse scores was 27.5% (17.8, 37.2), p < 0.001. There was a negative correlation between the average and percentage difference of the FibroScan® and Acoustic Radiation Force Impulse scores ( r (95% CI) = −0.41 (−0.57, −0.21), p < 0.001), thus showing that percentage difference gets smaller for greater FibroScan® and Acoustic Radiation Force Impulse scores. Body mass index was the biggest influencing factor on differences between FibroScan® and Acoustic Radiation Force Impulse ( r = 0.12 (0.01, 0.23), p = 0.05). Acoustic Radiation Force Impulse scores at segment 5/8 and the left lobe showed good correlation ( r (95% CI) = 0.83 (0.75, 0.89), p < 0.001). Conclusion: FibroScan® and Acoustic Radiation Force Impulse had similar predictive values for the assessment of liver stiffness in patients with chronic hepatitis C infection; however, the level of agreement varied across lower and higher scores.