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Neuroscience

Zebrafish as a Model for Schizophrenia

John Shengdao Chen ('08), Kevin Jones

The objective of this study was to establish the zebrafish, Danio rerio, as a model organism for the investigation of schizophrenia and antipsychotic medications. Zebrafish were exposed to MK801 3 dpf (days post fertilization) and hourly recordings were taken followed by daily recordings up to 9 dpf. Results show an acute increase in spontaneous locomotion followed by long-term effects after washout. MK801- treated zebrafish were also exposed to D1 and D2-specific dopamine antagonists to examine the roles of dopaminergic signaling in the effects of MK801 induced activity. SKF and sulpiride were found to have no effect on spontaneous locomotion of MK treated fish. Finally, a dose response curve for ziprasidone, an antipsychotic, was generated to find an optimal concentration to counteract the effects of MK801.
Funding provided by: SURP

Promising Future for Novel Antipsychotic

Kayleigh Haruka Kaneshiro ('10), Guochuan E. Tsai*
*Los Angeles Biomedical Research Institution, Harbor-UCLA Medical Center, Los Angeles, CA

A leading hypothesis (Javitt et.al., 1991) for schizophrenia targets the neurotransmission of the N-methyl- D-aspartate (NMDA) receptor selective for glutamate. Pharmaceutical companies are producing an array of novel drugs that target potential faulty steps of the NMDA neurotransmission. D-amino acid oxidase metabolizes the co-agonists of the NMDA receptors, D-alanine and D-serine. Sodium benzoate inhibits D- amino acid oxidase. We hypothesize that higher level of D-serine and D-alanine will be present in serum and brain tissue after the treatment of sodium benzoate. For this, we conduct two experiments: the first was the effectiveness of the drugs sodium benzoate on 31 physically healthy patients clinically diagnosed for schizophrenia. Their serum was subjected to chiral determination of HPLC to analyze the levels of D-serine and D-alanine. The second study looked at the CNS levels of the D-amino acids after sodium benzoate treatment on mice. In conclusion, if sodium benzoate inhibits the D-amino acid oxidase, higher levels of D-serine and D-alanine should be present in the human serum and/or mice brain tissue after the treatment and should raise the levels of D-alanine and D-serine; hence enhancing the NMDA neurotransmission which will benefit patients with schizophrenia.
Funding provided by: Los Angeles Biomedical Research Institute

Evidence of Altered Synaptic Transmission in PPT-1 Mutant Drosophila Melanogaster

Joyce Jungeun Kim ('09), Laura Johnson ('08), Sarah Jenkins ('08), Kelly Sinnott ('08), Karen Parfitt

Mutations in the gene for the enzyme PPT-1 are believed to cause NCL (neuronal ceroid lipofuscinosis), also known as Batten disease, a childhood neurodegenerative disease that affects 1 in 12,500 births. Previous research has shown that a PPT-1 deficiency leads to synaptic degradation. Using a Drosophila melanogaster model, we tested the hypothesis that PPT-1 mutations result in physiological changes at the level of the synapse. We measured ERG (electroretinogram) depolarizations to test the synaptic function of retinal cells and found no differences in PPT-1 mutants. Spontaneous miniature excitatory junction potential (EJP) recordings showed an increased frequency of events when compared to wild type for both the Df(1)446-20j null mutation and PPT-1 S77F point mutants, but no difference in amplitude, indicating a presynaptic change in vesicular release in those mutants. We intend to measure evoked EJPs in different concentrations of calcium in order to examine differences in calcium dependence of neurotransmitter vesicle release in the PPT-1 mutants, as well as apply high frequency stimulations to determine how fast the vesicle pool depletes and replenishes. Our results to date, however, support our hypothesis that PPT-1 mutations result in changes in the functions of nerve terminals, at least at the neuromuscular junction.
Funding provided by: SURP (Seaver - JJK); SURP (LJ); New Generation Scholarship Fund (Scripps College)

Ammonia Assay Is a Useful Measurement of Zebrafish Locomotive Activity

Dallis Jelani Clendeninn ('09), Kevin Jones

We intended to develop and refine a chemical assay that could be used to accurately monitor the behavioral activity of zebrafish larvae. Previous results from our lab showed that fish exposed to sub-anesthetic doses of the NMDA receptor antagonist, MK-801, exhibit an increase in spontaneous locomotion and sensitivity to vibratory stimuli. Acute exposure to MK801 rapidly elicits behavioral effects that persist for several days post exposure. Since animals excrete nitrogen as a by-product of metabolism (urea in humans, ammonia in zebrafish metabolism), we hypothesized that MK-801 exposed fish would excrete more ammonia than control fish due to the increased energy demands of increased locomotion. Ammonia levels were assayed by measuring glutamate dehydrogenase activity through its absorption rate at 340nm. The zerbrafish larvae, when exposed to MK-801, excreted about 60% more ammonia than vehicle fish. Furthermore, a significant increase in ammonia excretion could be detected for 4 days post drug exposure. This suggests the MK-801 causes an increase in metabolism, and that a chemical assay using glutamate dehydrogenase is effective at detecting these behavioral changes.
Funding provided by: SURP (Richter)

Research at Pomona