Abstract
Mice lacking the prion protein (PrPC) gene (Prnp), Ngsk Prnp 0/0 mice, show late-onset cerebellar Purkinje cell (PC) degeneration because of ectopic overexpression of PrPC-like protein (PrPLP/Dpl). Because PrPC is highly expressed in cerebellar neurons (including PCs and granule cells), it may be involved in cerebellar synaptic function and cerebellar cognitive function. However, no studies have been conducted to investigate the possible involvement of PrPC and/or PrPLP/Dpl in cerebellum-dependent discrete motor learning. Therefore, the present cross-sectional study was designed to examine cerebellum-dependent delay eyeblink conditioning in Ngsk Prnp 0/0 mice in adulthood (16, 40, and 60 weeks of age). The aims of the present study were two-fold: (1) to examine the role of PrPC and/or PrPLP/Dpl in cerebellum-dependent motor learning and (2) to confirm the age-related deterioration of eyeblink conditioning in Ngsk Prnp 0/0 mice as an animal model of progressive cerebellar degeneration. Ngsk Prnp 0/0 mice aged 16 weeks exhibited intact acquisition of conditioned eyeblink responses (CRs), although the CR timing was altered. The same result was observed in another line of PrPc-deficient mice, ZrchI PrnP 0/0 mice. However, at 40 weeks of age, CR incidence impairment was observed in Ngsk Prnp 0/0 mice. Furthermore, Ngsk Prnp 0/0 mice aged 60 weeks showed more significantly impaired CR acquisition than Ngsk Prnp 0/0 mice aged 40 weeks, indicating the temporal correlation between cerebellar PC degeneration and motor learning deficits. Our findings indicate the importance of the cerebellar cortex in delay eyeblink conditioning and suggest an important physiological role of prion protein in cerebellar motor learning.
Highlights
Sheep scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt–Jacob disease (CJD) in humans are variants of prion diseases, which are caused by infectious agents named prions [1,2,3,4,5]
We found age-dependent alterations of eyeblink conditioning in 2 indices: (i) conditioned eyeblink responses (CRs) incidence and (ii) the timing of CR expression
The CR incidence impairment in older Ngsk Prnp0/0 mice could be attributed to progressive degeneration of Purkinje cell (PC), indicating the importance of the cerebellar cortex in acquisition of eyeblink conditioning
Summary
Bovine spongiform encephalopathy (BSE), and Creutzfeldt–Jacob disease (CJD) in humans are variants of prion diseases, which are caused by infectious agents named prions [1,2,3,4,5]. Prion diseases may be expressed as genetic, infectious, or sporadic disorders, all of which involve modification of the normal cellular form of the prion protein (PrPC). PrPC-deficient mice generated by some of us (Ngsk Prnp0/0 mice) in which the functional PrP gene (Prnp), including the entire PrPcoding sequence of exon 3 and a part of intron 2 (900 bp), was deleted showed progressive symptoms of ataxic gait and hindquarter tremors late in life [13]. Late-onset ataxia is observed in 2 other independently derived lines of Prnp0/0 mice [9,11]. The other 2 lines of PrPC-deficient mice, including ZrchI Prnp0/0 mice, do not exhibit cerebellar degeneration [8,10]. Ectopic expression of the novel locus Prnd, which is 16 kb downstream of Prnp and encodes a 179-
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