Azam Asemi-Rad, Farshid Ghiyamihoor, G Giacomo Consalez, Hassan Marzban
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引用次数: 0
Abstract
Cerebellar nuclei (CN) constitute the sole cerebellar output to the rest of the central nervous system and play a central role in cerebellar circuits. Accumulating evidence from both human genetics and animal studies point to a crucial role for CN connectivity in neurological diseases, including several types of ataxia. However, because of the compact and restricted topography and close functional connection between the CN and the cerebellar cortex, identifying cerebellar deficits exclusively linked to CN is challenging. In this study, we have experimentally ablated large projection glutamatergic neurons of the lateral CN and evaluated the impact of this selective manipulation on motor coordination in mice. To this end, through stereotaxic surgery, we injected the lateral CN of Vglut2-Cre+ mice with an adeno-associated virus (AAV) encoding a Cre-dependent diphtheria toxin receptor (DTR), followed by an intraperitoneal injection of diphtheria toxin (DT) to ablate the glutamatergic neurons of the lateral nucleus. Double immunostaining of cerebellar sections with anti-SMI32 and -GFP antibodies revealed GFP expression and provided evidence of SMI32+ neuron degeneration at the site of AAV injection in the lateral nucleus of Vglut2-Cre+ mice. No changes were observed in Vglut2-Cre negative mice. Analysis of motor coordination by rotarod test indicated that the latency to fall was significantly different before and after AAV/DT injection in the Vglut2-Cre+ group. Elapsed time and number of steps in the beam walking test were significantly higher in AAV/DT injected Vglut2-Cre+ AAV/DT mice compared to controls. We demonstrate for the first time that partial degeneration of glutamatergic neurons in the lateral CN is sufficient to induce an ataxic phenotype.
期刊介绍:
Official publication of the Society for Research on the Cerebellum devoted to genetics of cerebellar ataxias, role of cerebellum in motor control and cognitive function, and amid an ageing population, diseases associated with cerebellar dysfunction.
The Cerebellum is a central source for the latest developments in fundamental neurosciences including molecular and cellular biology; behavioural neurosciences and neurochemistry; genetics; fundamental and clinical neurophysiology; neurology and neuropathology; cognition and neuroimaging.
The Cerebellum benefits neuroscientists in molecular and cellular biology; neurophysiologists; researchers in neurotransmission; neurologists; radiologists; paediatricians; neuropsychologists; students of neurology and psychiatry and others.