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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    254—Schizophrenia: Molecular and Cellular Mechanisms

    Sunday, November 10, 2013, 1:00 pm - 5:00 pm

    254.01: Reverse translation animal model of hippocampal dysfunction in Schizophrenia

    Location: Halls B-H

    *S. SOUTHCOTT, M. YANAGI, J. LISTER, I. LEE, C. TAMMINGA;
    Psychiatry, Univ. of Texas Southwestern Med. Ctr., Dallas, TX

    Abstract Body: Animal models for psychosis have been inadequate because the cellular and molecular characteristics of the condition itself have been obscure. As the disease neurobiology is advancing, it is becoming possible to develop animal models through reverse translation, mimicking the biology of the human condition. We have focused on modeling hippocampal pathology and its learning and memory component as it informs psychosis. In clinical studies of psychosis in schizophrenia, we show hippocampal hyperperfusion, GluN1 protein reduction, particularly in dentate gyrus (DG) and synaptic strengthening at the NIMDA receptor in CA3 along with alterations in relational memory capacity in the illness (Tamminga, et al., 2010 and 2012; Li, et al., 2012); these are the molecular and behavioral targets we have modeled in the animal. To explore a reverse translation animal model, we crossed a POMC-Cre mouse line with a floxed P-GluN1 mouse to create a DG-specific knock down of GluN1 protein in the animal. These animals have reduced levels of GluN1 restricted to DG (WT n=7; KO n=7). Behaviorally, these mice show decreased pre-pulse inhibition, reduced learning in the Morris Water Maze, increased freezing in a fear conditioning paradigm (Contextual FC p=0.04; Cued FC p=0.004) and an increased latency to respond in the passive avoidance paradigm (p=0.01). In tissue, we met the tissue phenotype of reduced GluN1 in DG but failed to generated the psychosis fingerprint of increased synaptic strengthen marker in CA3 at the NMDA receptor. However, we modified this animal model in several ways and have, in the end, been able to adapt this KO animal to show both the behavioral phenotype of psychosis (noted above) and molecular evidence reflecting both the DG GluN1 reduction and the psychosis finger-print (increased GluN2B: WT n=7; KO n=7; p=0.035) in CA3. We will include the full animal behavioral profile and the tissue bio-signature of this psychosis animal model.
    Li W, Potts B, Perez J, Ghose S, Tamminga C. Examining learning and memory plasticity in hippocampal subfields in schizophrenia. Poster session presented at: SFN 2012. Oct 13-17 2012; New Orleans, LA.
    Tamminga CA, Southcott S, Sacco C, Wagner AD, Ghose S. Glutamate dysfunction in hippocampus: relevance of dentate gyrus and CA3 signaling. Schizophr Bull. 2012 Sep;38(5):927-35.
    Tamminga CA, Stan AD, Wagner AD. The hippocampal formation in schizophrenia.
    Am J Psychiatry. 2010 Oct;167(10):1178-93.

    Lay Language Summary: Mouse models of schizophrenia have always been hard to validate. Schizophrenia is an illness that is defined, diagnosed and evaluated through the use of language. While there are some characteristic behaviors associated with schizophrenia, these are not specific enough to specify the illness. We have taken a reverse translational approach to building a mouse model of the illness that is designed to mimic its tissue changes and its regional functional pathology. One of the characteristics of schizophrenia in patients (one which correlates with psychosis) is increased neuronal activity in the hippocampus; it is a characteristic of the illness which has been consistently validated in several different laboratories. We have recently taken this hippocampal hyperactivity model and, using human postmortem schizophrenia tissue, described molecular correlates of the hyperactivity within hippocampal subfields. We found significant differences in hippocampal CA3 which are consistent with increased neuronal activity in hippocampus. This allows us to match both the functional characteristics of psychosis (ie, increased hippocampal neuronal activity) with the molecular correlates of those functional changes (ie, those reported here at the SFN meeting, which include increases in the GluN2B-containing NMDA receptors). This approach allows us to match pathology in the regional medial temporal lobe condition in the mouse model with pathology in schizophrenia. We have used these findings from human tissue and in vivo imaging to translate them into a mouse which can be manipulated in many more ways than human subject experimentation.
    Human studies of psychosis in schizophrenia, show hippocampal hyperperfusion, normally correlated with increased regional neuronal activity. As well, we have found reduced GluN1 protein, the obligate subunit for NMDA receptor function, selectively expressed in dentate gyrus (DG), leading to reduced neuronal activity in DG and in the mossy fiber pathway to CA3. In CA3, we find synaptic strengthening at the NMDA receptor, represented by increased GluN2B-containing NMDA receptors and an increase in the GluN2B/GluN2A ratio (Tamminga, et al., 2010 and 2012; Li, et al., 2012). Therefore, the combination of decreased GluN1 in DG and increased GluN2B/GluN1, BDNF, and PSD95 (all related proteins we have shown increased in CA3) are the molecular targets we have modeled in the mouse along with behaviors representing decreased learning and memory in the mouse.
    We used the available DG-specific GluN1 knockout mouse (McHugh, et al 2007) and paired this with subacute 1 month administration of PCP, a usual psychomimetic drug, and have demonstrated increased GluN2B protein in CA3. Behaviorally, these mice show decreased pre-pulse inhibition, reduced learning in the Morris Water Maze, increased freezing in a fear conditioning paradigm and an increased latency to respond in the passive avoidance paradigm, all behaviors demonstrating hippocampal dysfunction in the mice, behaviors which correspond to decreased declarative memory function in persons with schizophrenia. In addition, we are now looking at the effects of adding the effect of genetic risk genes by crossing our GluN1 deficient mice with schizophrenia risk gene mutants.
    Schizophrenia is a highly complex, debilitating disease with an unknown etiology or mechanisms therefore it is important to study. However, this study has been difficult because the illness affects many brain regions and generates a complexity and a heterogeneous set of symptoms. Animal models for psychosis have been inadequate because the cellular and molecular characteristics of the condition itself have been obscure. As the disease neurobiology is advancing, it is becoming possible to develop animal models through reverse translation, mimicking the biology of the human condition.