Prof. Kohichi Tanaka
ISP2012 Lecture Course Abstract:
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Genetic animal models of Neuropsychiatric disorders
Despite massive research efforts, the pathogenesis and pathophysiology of neuropsychiatric disorders remain largely unknown. Although modeling of human neuropsychiatric disorders in animals is challenging, animal models are necessary for understanding disease pathophysiology and for developing the treatments. This lecture will cover the validation and use of animal models of neuropsychiatric disorders. Neuropsychiatric disorders focused will include obsessive-compulsive disorder (OCD) and glaucoma.
There is s a growing body of evidence implicating an increased ratio of excitation/inhibition in the pathophysiology of neuropsychiatric disorders including schizophrenia, OCD, autism and glaucoma. Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system. In order to ensure normal neurotransmission, the extracellular glutamate concentration is controlled mainly by glial glutamate transporters GLT1 and GLAST. We generate animal models for neuropsychiatric disorders, in which a ratio of excitation/inhibition is increased by genetic down-regulation of glial glutamate transporters. Downregulation of glial glutamate transporters results in decreased uptake of glutamate and elevated glutamate overstimulates glutamate receptors.
I show the glutamate transporters GLT1 conditional knockout mice (GLT1 cKO mice) exhibit physical tics and compulsive grooming behavior leading to facial hair loss and skin lesions; these behavioral abnormalities are considered as autism spectrum disorders (ASDs) and OCD-like behaviors. In contrast, GLT1 cKO mice do not show increased anxiety-like behavior, other OCDs-like behavior, or ASDs-like impaired social behavior. Electrophysiological studies reveal increased excitatory neurotransmission during repetitive stimulation in cortico-striatal synapse. Furthermore, treatment of memantine, an open channel blocker of NMDA-type glutamate receptor, rescues excessive grooming and physical tics. These findings demonstrate glutamatergic hyperactivity in cortico-striatal synapse due to the dysfunction of GLT1 is important for pathogenesis of compulsive-repetitive behaviors.
I also show that mice deficient in the glutamate transporters GLAST demonstrate spontaneous retinal ganglion cell (RGC) and optic nerve degeneration despite exhibiting normal intraocular pressure (IOP). In GLAST-deficient mice, both glutamate excitotoxicity and oxidative stress contribute to RGC degeneration. These mice are the first animal models of normal tension glaucoma (NTG) that offer a powerful system for investigating mechanisms of neurodegeneration in NTG. Next, we investigated whether GLAST mutations play roles in human glaucoma phenotypes. We identified two novel missense mutations that decreased a capacity for glutamate uptake. These results suggest that heterozygous mutations in GLAST can lead to decreased glutamate uptake, which can contribute to RGC loss in some glaucoma patients. Furthermore, arundic acid that enhances GLAST expression, can rescue RGC death in GLAST heterozygous mice, suggesting that enhancing the function of GLAST may be useful for the treatment of glaucoma.
Thus, useful animal models can serve as essential tools for examining the etiology and treatment of neuropsychiatric disorders.