The role of synaptic phosphoprotein, Synapsin, in schizophrenia.

AUTHOR: Luke Molinaro

Schizophrenia is a costly, debilitating psychiatric illness affecting approximately 1.1% of the world’s population. The disorder is characterized by positive (hallucinations, paranoia), negative (social withdrawal, lack of motivation), and cognitive (memory impairments, attention deficits) symptoms. A number of genome-wide scans, meta-analyses, and genetic susceptibility studies have implicated the synapsin II gene (3p25) in the etiology of schizophrenia and other psychiatric disorders, and have found a reduction of synapsin II mRNA and protein in the prefrontal cortex of schizophrenic post-mortem samples. Synapsin II is a member of the neuronal phosphoprotein family and are evolutionarily conserved across many organisms. These proteins are important in a variety of synaptic functions, including synaptogenesis and the regulation of neurotransmitter release. Disruptions in the expression of synapsins lead to synaptic dysfunction, which can result in neurotransmitter imbalances, likely contributing to the pathophysiology of schizophrenia. The involvement of the synapsin family, specifically synapsin II, in the pathophysiology of schizophrenia may provide insight into improved diagnostics and novel targets for therapeutic intervention.

Citation: Molinaro, L. P., Hui, P., Tan, M., & Mishra, R. K. (2015) World Journal of Psychiatry. In Press.

Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

AUTHOR: Jay Patel

Acting as a diffusion barrier, the blood brain barrier (BBB) is composed primarily of brain endothelial cells, astrocyte end-feet, pericytes, perivascular macrophages, and a basal membrane. Its barrier is a result of a tightly sealed monolayer of endothelial cells with tight junctions and adherens junctions forming the seal between cells at junctional complexes. The BBB regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease, multiple sclerosis, and even schizophrenia. Inflammation and oxidative stress have also been implicated in the pathophysiology of bipolar disorder (BD). Here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species) substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. Assessing BBB integrity and the effects of current BD medication, including lithium, on BBB protection and recovery can not only advance the knowledge on the neurobiology of BD but also open numerous possibilities to investigate new treatment pathways for this devastating major mental illness.

Citation: Patel, J. P., & Frey, B. N. (2015) Neural Plasticity DOI: 10.1155/2015/708306

AUTHORS: Siu C, Balsor J, Jones D, Murphy K

Summary: Caitlin Siu

Myelin is typically thought of as insulation, but recent studies show it also plays roles in neuroplasticity, axonal metabolism, and neuroimmune signalling. Myelin is complex, and composed of many proteins, with Myelin Basic Protein (MBP) being the most studied. MBP has 2 families: Classic-MBP, necessary for activity-driven compaction of myelin around axons; and Golli-MBP, found in neurons, oligodendrocytes, and T-cells, called a “molecular link” between the nervous and immune systems. In visual cortex, myelin proteins interact with immune cells to affect experience-dependent plasticity. We studied myelin in human visual cortex using Western blotting to quantify Classic- and Golli-MBP expression in post-mortem samples ranging from 20 days to 80 years old. We found that Classic- and Golli-MBP have different patterns of change across the lifespan. Classic-MBP increases up to 42 years and then declines into aging. Golli-MBP has early developmental changes that coincide with milestones in visual system sensitive period, and gradually increases into aging. There are three stages in the balance between Classic- and Golli-MBP expression, with Golli-MBP dominating early, then shifting to Classic-MBP, and back to Golli-MBP in aging. Golli-MBP has a wave of high inter-individual variability during childhood. These results are timely because they complement recent advances in MRI techniques that produce high resolution maps of cortical myelin in normal and diseased brain. The pattern of Golli-MBP across the lifespan suggests it supports high neuroimmune interaction in cortical development and in aging. 

AUTHORS: Rosa E, Fahnestock M 

Summary: Elyse Rosa

Alzheimer’s disease (AD) is characterized by accumulation of extracellular amyloid-β (Aβ), which eventually leads to synaptic dysfunction, memory loss and cognitive decline. However, the toxic mechanism is not well understood. One theory suggests that amyloid-β leads to cognitive dysfunction by diminishing trophic support for affected neurons. This has been supported by findings that brain- derived neurotrophic factor (BDNF) mRNA and protein levels are significantly down-regulated in AD (Garzon, et al., 2002; Holsinger, et al., 2000; Michalski & Fahnestock 2003). Previous work has demonstrated that Aβ decreases activity-induced BDNF transcription by regulating cyclic AMP response element binding protein (CREB) activation via phosphorylation. However, the specific mechanism by which Aβ reduces basal BDNF expression remains unclear. We found that differentiated, unstimulated human neuroblastoma (SH-SY5Y) cells treated with oligomeric Aβ exhibited a significant reduction of basal BDNF expression and significantly reduced CREB mRNA compared to controls. Total CREB protein was decreased in both the cytoplasm and nucleus of Aβ-treated cells. However, neither the levels of activated CREB (pCREB133) nor inactivated CREB (pCREB129) were altered relative to total CREB levels. The PKA activator forskolin increased CREB activity and prevented Aβ-induced basal BDNF loss when administered prior to Aβ but did not rescue BDNF expression when administered later. These data demonstrate a new mechanism for Aβ-induced BDNF down-regulation: in the absence of cell stimulation, Aβ down-regulates basal BDNF levels via Aβ-induced CREB transcriptional down-regulation, not changes in CREB phosphorylation. Thus, Aβ reduces basal and activity-induced BDNF expression by different mechanisms. 

Two-point orientation discrimination versus the traditional two-point test for tactile spatial acuity assessment

SUMMARY: Jonathan Tong 

For decades, neurologists have used two-point discrimination (2PD) as a tool for diagnosing neurological dysfunction. 2PD involves stimulating a patient with the tips of a caliper and asking: "were you touched with two points or one?" As the separation between tips decreases to zero, so too should the patient's probability of responding "two-points"; the reasoning for this is that two points  that fall between adjacent touch receptors should not be reliably distinguishable from a single point between these same receptors. Remarkably, many patients are able to reliably distinguish two points from one, even when the two points have zero separation (Johnson & Phillips, 1981). This "hyperacuity" might be explained by the fact that a single receptor neuron fires a greater number of impulses to a single indentation than to a double indentation of the same depth (Vega-Bermudez & Johnson, 1999), thus leading to a magnitude difference that the brain can use to discriminate two points at extremely small spacing. We have designed a new clinical screening test that avoids this "magnitude-cue" confound: by having patients identify the orientation of two-point stimuli (horizontal or vertical) in a two-point orientation discrimination (2POD) task, patients must rely on purely spatial information to discern orientation. As expected for a true measure of spatial acuity, 2POD performance approaches chance levels at zero separation, unlike the 2PD task. We recommend replacing the 2PD task with 2POD in clinical settings.

SUMMARY: Ritesh Daya 

Functional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia. Acute treatment at 0.5 mg/kg disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat. 
These findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals.