Adult heterozygous Lurcher mice show a degeneration of almost all Purkinje cells and 90% of the granular cells of the cerebellum, resulting in ataxia or general deficits in motor coordination. These mice are therefore an excellent model for studying the role of the cerebellar cortex in motor performance, including the acquisition of new motor abilities. The performance of 3-month-old Lurcher mice was studied in various behavioural (fall, horizontal bar, rotating cylinder, and ladder), spatial orientation (water maze) and associative learning (eyelid classical conditioning) tasks and compared with that of wild-type mice. Behavioural tasks indicated a deficit for motor abilities in Lurcher mice but with some adaptation to the tests and improvement in performance. Wild-type and Lurcher mice performed swimming equally, but the latter learned the task significantly more slowly than the former. The late component of reflex blinks was smaller in amplitude and had a longer latency in Lurcher mice than in controls. Learning curves for Lurcher mice during classical conditioning of eyelid responses were similar to controls, but the amplitude of the learned response in Lurcher mice was significantly lower. The startle response to a severe tone was similar in both control and Lurcher mice but the latter were unable to produce prepulse inhibition. These results suggest that the cerebellar cortex is not indispensable for the performance of this complete set of skeletal and facial tasks, or for the acquisition of new motor abilities, but it is for the appropriate execution and adjustment of any of these motor activities.

Transgenic mice over-expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimer's disease (V642I, so-called London mutation, hereafter APPLd2) and wild-type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques. Both 3- and 10-month-old APPLd2 mice had reflex eyelid responses like those of controls, but only younger mice were able to acquire a classical conditioning of eyelid responses in a trace paradigm. In vitro studies on hippocampal slices showed that 10-month-old APPLd2 mice also presented deficits in paired-pulse facilitation and long-term potentiation, but presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals. It is proposed that definite functional changes may appear well in advance of noticeable structural alterations in this animal model of Alzheimer's disease, and that specific learning tasks could have a relevant diagnostic value.

Porras-García E, Sánchez-Campusano R, Martínez-Vargas D, Domínguez-del-Toro E, Cendelín J, Vožeh F, Delgado-García JM. Behavioral characteristics, associative learning capabilities, and dynamic association mapping in an animal model of cerebellar degeneration. J Neurophysiol 104: 346 -365, 2010. First published April 21, 2010 doi:10.1152/jn.00180.2010. Young adult heterozygous Lurcher mice constitute an excellent model for studying the role of the cerebellar cortex in motor performance-including the acquisition of new motor abilities-because of the early postnatal degeneration of almost all of their Purkinje and granular cells. Wild-type and Lurcher mice were classically conditioned for eyelid responses using a delay paradigm with or without an electrolytic lesion in the interpositus nucleus. Although the late component of electrically evoked blink reflexes was smaller in amplitude and had a longer latency in Lurcher mice than that in controls, the two groups of animals presented similar acquisition curves for eyeblink conditioning. The lesion of the interpositus nucleus affected both groups of animals equally for the generation of reflex and conditioned eyelid responses. Furthermore, we recorded the multiunitary activity at the red and interpositus nuclei during the same type of associative learning. In both nuclei, the neural firing activity lagged the beginning of the conditioned response (determined by orbicularis oculi muscle response). Although red nucleus neurons and muscle activities presented a clear functional coupling (strong correlation and low asymmetry) across conditioning, the coupling between interpositus neurons and either red nucleus neurons or muscle activities was slightly significant (weak correlation and high asymmetry). Lurcher mice presented a nonlinear coupling (high asymmetry) between red nucleus neurons and muscle activities, with an evident compensatory adjustment in the correlation of firing between interpositus and red nuclei neurons (a coupling with low asymmetry), aimed probably at compensating the absence of cerebellar cortical neurons.

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Fatty acids and glucose are the main bioenergetic substrates in mammals that are alternatively used during the transition between fasting and feeding. Impairment of mitochondrial fatty acid oxidation causes mitochondrial myopathy leading to decreased physical performance. Here, we report that haploinsufficiency of ADCK2, a member of the aarF domain-containing mitochondrial protein kinase family, in human is associated with liver dysfunction and severe mitochondrial myopathy with lipid droplets in skeletal muscle. In order to better understand the etiology of this rare disorder, we generated a heterozygous Adck2 knockout mouse model to perform in vivo and cellular studies using integrated analysis of physiological and omics data (transcriptomics-metabolomics). The data show that Aldh2+/- mice exhibits impaired fatty acid oxidation, liver dysfunction, and mitochondrial myopathy in skeletal muscle resulting in lower physical performance. Significant decrease in CoQ biosynthesis was observed and supplementation with CoQ partially rescued the phenotype both in the human subject and mouse model. These results indicate that ADCK2 is involved in organismal fatty acid metabolism and in CoQ biosynthesis in skeletal muscle. We propose that patients with isolated myopathies and myopathies involving lipid accumulation be tested for possible ADCK2 defect as they are likely to be responsive to CoQ supplementation.