| Abstract No.: | B-C2122 |
| Country: | Canada |
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| Title: | EARLY AND LATE EFFECTS OF THE HUNTINGTON’S DISEASE MUTATION UPON CORTICOSTRIATAL FUNCTION: ALTERATIONS TO NMDA-RECEPTOR LOCALIZATION, FUNCTION AND NEURONAL NETWORK SIGNALING |
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| Authors/Affiliations: | 2 Austen Milnerwood*; 2 Joshua Levinson; 1 Ainsley Coquinco; 3 Ashley George; 2 Alaa El-Husseini; 1 Max Cynader; 2 Timothy Murphy; 2 Lynn Raymond;
1 Brain Research Centre, UBC; 2 Psychiatry, Brain Research Centre, UBC; 3 Psychiatry, UBC; Vancouver,BC, Canada
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| Content: | Objectives: Huntington’s disease (HD) is a late-onset, progressive and fatal disease resulting from a CAG repeat mutation producing an expanded polyglutamine (polyQ) tract (>35) in the protein huntingtin (htt); age of onset is inversely correlated with CAG repeat length. Clinically, HD is characterized by early cognitive and emotional disturbances and later severe movement disorder. Progressive neurodegeneration occurs, with a dramatic loss of striatal medium-sized spiny GABAergic projection neurons (MSNs). Evidence suggests the over-activation of N-methyl-D-aspartate glutamate receptors (NMDARs) contributes to neurodegeneration in HD. We recently reported specific alterations to presynaptic function and postsynaptic NMDAR signaling in pathogenic repeat length-expressing mice (YAC72 & YAC128 line 55) months prior to phenotypic onset, with respect to non-pathogenic repeat length controls (YAC18). Furthermore, mice expressing high levels of polyQ-expanded htt (YAC128 line 53) exhibit additional synaptic dysfunction; manifest as altered AMPA receptor signaling. As NMDARs are crucial to a wide range of normal physiological processes, broad pharmaceutical intervention against their activity has limited benefits and major side effects. NMDAR trafficking is tightly controlled by increasingly well defined cellular processes, thus a greater understanding of mutant htt-induced alterations to NMDAR localization may provide novel therapeutic targets to delay onset and prevent symptom progression and cell death in HD. The current study aimed to further determine the nature of altered NMDAR signaling and corticostriatal dysfunction before, during and after phenotype onset.
Materials and methods: Standard whole-cell and field electrophysiology was conducted in acute coronal slices prepared from 1-month old YAC18,72,128 and C6R transgenic mice. Spontaneous and stimulus evoked AMPA- and NMDA-R glutamatergic transmission was assessed in normal recording conditions prior to investigations that maximized NMDAR activation and used glutamate uptake inhibitors to study extrasynaptic current. Corticostriatal co-cultures were grown for ~14DIV for immunocytochemical investigation of NMDAR and PSD-95 localisation. Voltage-sensitive dye loaded corticostriatal slices were used for optical recording of evoked neuronal network activity across large areas of both cortex and striatum at 1, 6 & 12 months.
Results: We provide several lines of evidence that demonstrate elevated extrasynaptic NMDAR signaling in HD mice. The underlying causal mechanisms, as well as the consequences and perturbations to network activity are also discussed.
Conclusions: Extrasynaptic NMDAR signaling has been shown elsewhere to activate a dominant CREB shut-off pathway, which has been interpreted as a cell death signal. Our observations of elevated extrasynaptic NMDAR current in mice suggest that early perturbations to NMDAR signaling associated with mutant htt expression may underlie symptom progression and eventual cell death in HD. These developments offer highly specific candidates for therapeutic targets with which to delay onset and progression of this devastating disease. |
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