Browsing by Subject "Receptors, N-Methyl-D-Aspartate"
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Item A Reverse Translation Mouse Model for Schizophrenic Psychosis: Contribution of Hippocampal Subfield Pathology(2016-11-30) Southcott, Sarah Ann; Hsieh, Jenny; Huber, Kimberly M.; Rothenfluh, Adrian; Tamminga, CarolSchizophrenia is a serious and lifelong psychotic illness that affects all aspects of cognitive and affective function and whose etiology and brain mechanisms remain elusive. Schizophrenia affects not only those who express the condition, but also their family members, friends, and society as a whole. There is a worldwide prevalence of 1%, and the illness in 2012 alone, cost the USA an estimated $62.7 billion in medical care cost and lost wages. Schizophrenia is an extremely complex disease with a heterogeneous mixture of symptoms, including cognitive dysfunction, mood dysfunction, negative symptoms, and the defining symptom set, positive psychotic symptoms. The antipsychotic effects of dopamine receptor antagonists led people to hypothesize that schizophrenia is a disorder of dopamine hyperfunction, but considerable research has generated no strong evidence to support such a simple mechanistic hypothesis. Most recently, the glutamate system has become an etiologic focus in schizophrenia research and its research is proving more promising. We have studied the molecular basis of psychosis in human post mortem hippocampus in schizophrenia, and its related proteins important for learning and memory, especially the n-methyl-d-aspartate (NMDA) glutamate receptor system. Based on our findings we have developed a testable hypothesis of psychosis, formulated as a learning and memory disorder. In order to fully test this hypothesis we first needed to create a dynamic animal model based on our tissue findings that could be manipulated and probed. We found that knocking out the obligate subunit (GluN1) of the NMDA receptor selectively in the dentate gyrus paradoxically led to an increase in neuronal activity in the CA3 and several behavioral changes parallel to those we observe in schizophrenia. Furthermore we combined a pharmacological risk factor (phencyclidine) and a genetic risk factor (DISC1) with the knockout mouse that we believed would have the highest probability of interacting in a manner reminiscent of schizophrenia. These particular combinations did not exacerbate the symptoms of the dentate gyrus-specific GluN1 knockout mouse. Now we plan to use this dynamic mouse preparation to study the mechanisms whereby the reduction in GluN1 protein in dentate gyrus sensitizes and stimulates neuronal activity downstream within the hippocampus to better understand psychosis processes.Item Spontaneous Neurotransmission as a Driver of Calcium Signaling(2016-09-20) Reese, Austin Lowell; Kim, Tae-Kyung; Kavalali, Ege T.; Monteggia, Lisa; Bezprozvanny, IlyaSpontaneous neurotransmission is a stochastic mode of neurotransmitter release that is not coupled to action potential arrival at the presynapse. Recent evidence has shed light upon the presynaptic and vesicular fusion machinery that makes this mode of release unique to action potential driven, or evoked release, yet the postsynaptic reception of these differing signals has yet to be probed in detail. Here, I illustrate that evoked and spontaneous release modes coexist within the same synapses, yet the neurotransmitter released falls upon separate subsets of postsynaptic receptors. As a consequence of this phenomenon, in glutamatergic hippocampal synapses the NMDA receptors activated by spontaneous release are able to drive large calcium transients that maintain synaptic homeostasis and suppress local protein synthesis.