A new mechanism for antiepileptic drug action: vesicular entry may mediate the effects of levetiracetam. J Neurophysiol 106: 1227-1239, 2011. First published June 8, 2011 doi:10.1152/jn.00279.2011 is one of the most commonly prescribed antiepileptic drugs, but its mechanism of action is uncertain. Based on prior information that LEV binds to the vesicular protein synaptic vesicle protein 2A and reduces presynaptic neurotransmitter release, we wanted to more rigorously characterize its effect on transmitter release and explain the requirement for a prolonged incubation period for its full effect to manifest. During whole cell patch recordings from rat hippocampal pyramidal neurons in vitro, we found that LEV decreased synaptic currents in a frequency-dependent manner and reduced the readily releasable pool of vesicles. When we manipulated spontaneous activity and stimulation paradigms, we found that synaptic activity during LEV incubation alters the time at which LEV's effect appears, as well as its magnitude. We believe that synaptic activity and concomitant vesicular release allow LEV to enter recycling vesicles to reach its binding site, synaptic vesicle protein 2A. In support of this hypothesis, a vesicular "load-unload" protocol using hypertonic sucrose in the presence of LEV quickly induced LEV's effect. The effect rapidly disappeared after unloading in the absence of LEV. These findings are compatible with LEV acting at an intravesicular binding site to modulate the release of transmitter and with its most marked effect on rapidly discharging neurons. Our results identify a unique neurobiological explanation for LEV's highly selective antiepileptic effect and suggest that synaptic vesicle proteins might be appropriate targets for the development of other neuroactive drugs.epilepsy; synaptic vesicle protein 2A; synaptic vesicle release; hippocampal slice LEVETIRACETAM (LEV) IS AN antiepileptic drug (AED) with a unique mode of action and efficacy against focal and generalized seizures. The exact mechanism by which this drug reduces seizures is still under investigation. LEV does not inhibit voltage-gated Na ϩ channels (Zona et al. 2001), nor does it modulate GABA receptors (Margineanu and Klitgaard 2003), two common AED mechanisms. It is established that LEV binds to a presynaptic protein, synaptic vesicle protein 2A (SV2A), located in the membrane of synaptic vesicles (Lynch et al. 2004). The precise function of SV2A is also unknown, but studies of cultured neurons from SV2A knockout mice show a reduced postsynaptic response, due to a lower initial vesicle release probability (Custer et al. 2006) and a decrease in the total amount of neurotransmitter release during a stimulus train compared with controls (Chang and Sudhof 2009).Because SV2A plays a modulatory, but not essential, role in neurotransmission, it is unclear how a ligand binding to SV2A might alter neurotransmitter release.The cellular mechanism of action of LEV remains paradoxical. While it seems to do nothing to normal synaptic transmission, i...

Intraplate volcanism initiated shortly after the cessation of Cenozoic seafloor spreading in the South China Sea (SCS) region, but the full extent of its influence on the Indochina block has not been well constrained. Here we present major and trace element data and Sr-Nd-Pb-Hf isotope ratios of late Cenozoic basaltic lavas from the Khorat plateau and some volcanic centers in the Paleozoic Sukhothai arc terrane in Thailand. These volcanic rocks are mainly trachybasalts and basaltic trachyandesites. Trace element patterns and Sr-Nd-Pb-Hf isotopic compositions show that these alkaline volcanic lavas exhibit oceanic island basalt (OIB)-like characteristics with enrichments in both large-ion lithophile elements (LILE) and high field strength elements (HFSEs). Their mantle source is a mixture between a depleted Indian MORB-type mantle and an enriched mantle type 2 (EMII). We suggest that the post-spreading intraplate volcanism in the SCS region was induced by a Hainan mantle plume which spread westwards to the Paleozoic Sukhothai arc terrane.

Background: Protein prenylation may play an important role in Alzheimer disease. Results: Haplodeficiency in farnesyltransferase and geranylgeranyltransferase-1 attenuates neuropathology, but only reduction of farnesyltransferase rescues cognitive function in Alzheimer mice. Conclusion: Protein farnesylation and geranylgeranylation differentially affect the course of Alzheimer disease. Significance: Specific inhibition of protein farnesylation might be a potential strategy for effectively treating Alzheimer disease.

Neuropsychiatric symptoms and mental illness are commonly present in patients with chronic systemic diseases. Mood disorders, such as depression, are present in up to 50% of these patients, resulting in impaired physical recovery and more intricate treatment regimen. Stress associated with both physical and emotional aspects of systemic illness is thought to elicit detrimental effects to initiate comorbid mental disorders. However, clinical reports also indicate that the relationship between systemic and psychiatric illnesses is bidirectional, further increasing the complexity of the underlying pathophysiological processes. In this review, we discuss the recent evidence linking chronic stress and systemic illness, such as activation of the immune response system and release of common proinflammatory mediators. Altogether, discovery of new targets is needed for development of better treatments for stress-related psychiatric illnesses as well as improvement of mental health aspects of different systemic diseases.

Chromosomal rearrangement (CR) events result from abnormal breaking and rejoining of the DNA molecules, or from crossing-over between repetitive DNA sequences, and they are involved in many tumor and non-tumor diseases. Investigations of disease-associated CR events can not only lead to important discoveries about DNA breakage and repair mechanisms, but also offer important clues about the pathologic causes and the diagnostic/therapeutic targets of these diseases. We have developed a database of Chromosomal Rearrangements In Diseases (dbCRID, http://dbCRID.biolead.org), a comprehensive database of human CR events and their associated diseases. For each reported CR event, dbCRID documents the type of the event, the disease or symptoms associated, and—when possible—detailed information about the CR event including precise breakpoint positions, junction sequences, genes and gene regions disrupted and experimental techniques applied to discover/analyze the CR event. With 2643 records of disease-associated CR events curated from 1172 original studies, dbCRID is a comprehensive and dynamic resource useful for studying DNA breakage and repair mechanisms, and for analyzing the genetic basis of human tumor and non-tumor diseases.