Effect Of Sleep Deprivation On Cerebral PrP~C Expression And The Possiblce Role Of PrP~C In Sleep Deprivation Induced Cognitive Impairment

The correlation between sleep deprivation and memory impairment has beenconfirmed in many studies, but the underlying mechanisms remain unclear. Previousstudies indicate cellular prion protein(PrP~C) plays an important role in sleep regulationand memory and has multifaceted relationship with Alzheimer's disease(AD), a diseasecharacterized by memory decline. Herein, we hypothesized that PrP~Cplays a role inspatial memory impairment induced by sleep deprivation.Male adult Sprague-Dawley rats were randomly divided into three groups: cagecontrol group(CC group), tank control group(TC group), sleep deprivation group(SDgroup). Rats were deprived of sleep for72h using the modified multiple platformmethod. Morris water maze task was used to assess hippocampal-dependent spatialmemory. After sleep deprivation and Morris water maze test, rats were sacrificed andbrain tissue was analyzed for the levels of PrP~Cusing western blot. We also additionallyinvestigated the PrP~Cexpression in the frontal cortex,occipital cortex,temporal cortex,hippocampus and thalamus of the normal rats brain using western blot to gain a overallimpression of the regional distribution of PrP~C. Our data showed that the expression ofPrP~Cin hippocampus and thalamus is significantly higher than that in the frontal cortex,occipital cortex and temporal cortex of the normal rats brain which suggested itspotential role in regulating the functions of hippocampus and thalamus. We confirmedthat72-h sleep deprivation impaired spatial memory of rats, which is consistent with theearlier studies. Meanwhile, the PrP~Cexpression in rat hippocampus was selectivelysignificantly decreased.CREB is known to be a critical modulator of hippocampal-dependent learning,memory storage and synaptic plasticity. It has been shown that p-CREB levels increase inthe hippocampus following learning and reduce after sleep deprivation in rats, suggestingthat CREB phosphorylation plays a role in sleep deprivation induced cognitiveimpairment. Previous work in many laboratories have provided evidence that PrP~Crelatesto a variety of signal pathways including cAMP/PKA, MAPK, PI3-K/Akt and solublenon-receptor tyrosine kinase pathways. Whether PrP~Ccould modulate CREBphosphorylation in hippocampus has not been reported. With the purpose of exploringfurther the possible signaling function of PrP~Cin sleep deprivation induced memoryimpairment, p-CREB expression was examined after sleep deprivation in hippocampus, frontal cortex and thalamus using western blot and immunofluorescence technique andwas also examined after lentivector-mediated RNA interference of PrP~Cin primarycultured rats hippocampal neurons using western blot. After72-h sleep deprivation, theexpression of p-CREB in hippocampus but not in frontal cortex and thalamussignificantly decreased. Immunofluorescence showed that a small number of p-CREBpositive cells were observed in dentate gyrus of the hippocampus in SD group comparedwith control groups. Using lentiviral shRNA to knockdown PrP~Cin primary culturedhippocampal neurons, we found the expression of p-CREB decreased significantly.Previous studies strongly indicate that adult hippocampal newborn neurons areinvolved in learning and memory. The first important morphological change in neuronaldifferentiation involves the formation and growth of an axon, which permits the transferof information between neurons. Sophisticated central nervous system activities, such aslearning and memory, depend more on information transfer between neurons than otheractivities. PrP~Cplays a role in axon elongation has been indicated in previous studies. Tostudy the effect of low level PrP~Con axon elongation, axon length was examined afterlentivector-mediated RNA interference of PrP~Cin primary cultured rats hippocampalneurons using immunofluorescence technique. The result showed the length of axonsignificantly decreased7days after targeting of PrP~Cby RNA interference comparedwith controls.In conclusion, we speculated that PrP~Cin the hippocampus plays a role in sleepdeprivation induced hippocampal dependent spatial memory impairment in rats and oneof the involved pathways may be the CREB signal pathway. The inhibition of axongrowth may be the material basis directly leading to the cognitive impairment. Theseresults might partially explain the mechanisms of the effects of sleep deprivation oncognition. It is inviting to further uncover the upstream and downstream events in future.In light of this, PrP~C, CREB and axon elongation may be potential targets for thetreatment of memory impairment caused by sleep deprivation.