Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of proteinprotein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein-protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P ¼ 0.015) and syntaxin was 26% lower (P ¼ 0.006) in the VMC. In contrast, in the same region, SNARE protein-protein interactions were higher in schizophrenia (P ¼ 0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P ¼ 0.003), syntaxin (mean 18%, P ¼ 0.010), and VAMP (mean 16%, P ¼ 0.001), whereas clozapine increased only the VAMP level (mean 13%, P ¼ 0.004). Neither drug altered SNARE protein-protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.

The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown. The aim of this study was to identify alterations in protein and metabolite levels in the ALIC in schizophrenia. Samples were obtained post-mortem from individuals with schizophrenia (n=15) and non-psychiatric controls (n=13). Immunoreactivity for the myelin-associated protein myelin basic protein (MBP), and the axonal-associated proteins phosphorylated neurofilament and SNAP-25 was measured by enzyme-linked immunoadsorbant assay (ELISA). Metabolite concentrations were quantified by proton nuclear magnetic resonance (1H NMR) spectroscopy. Levels of myelin- or axonal-associated proteins did not differ between groups. Overall differences in metabolite concentrations were observed between the two groups (MANOVA F=2.685, p=0.036), with post-hoc tests revealing lower lactate (19%) and alanine (24%) levels in the schizophrenia group relative to controls. Observed changes in lactate and alanine levels indicate metabolic abnormalities within the ALIC in schizophrenia.

The knowledge about the diffuse axonal injury (DAI) as a clinicopathological entity has matured in the last 30 years. It has been defined clinically (immediate and prolonged unconsciousness leading to death or severe disability) and pathologically (the triad of DAI specific changes). In terms of its biomechanics, DAI is occurring as a result of acceleration forces of longer duration and has been fully reproduced experimentally.In the process of diagnosing DAI, the performance of a complete forensic neuropathological examination is essential and the immunohistochemistry method using antibodies against β-amyloid precursor protein (β-APP) has been proved to be highly sensitive and specific, selectively targeting the damaged axons.In this review, we are pointing to the significant characteristics of DAI as a distinct clinicopathological entity that can cause severe impairment of the brain function, and in the forensic medicine setting, it can be found as the concrete cause of death. We are discussing not only its pathological feature, its mechanism of occurrence, and the events on a cellular level but also the dilemmas about DAI that still exist in science: (1) regarding the strict criteria for its diagnosis and (2) regarding its biomechanical significance, which can be of a big medicolegal importance.

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