Genetic evidence for a role for protein kinase A in the maintenance of sleep and thalamocortical oscillations.
OBJECTIVE
Genetic manipulation of cAMP-dependent protein kinase A (PKA) in Drosophila has implicated an important role for PKA in sleeplwake state regulation. Here, we characterize the role of this signaling pathway in the regulation of sleep using electroencephalographic (EEG) and electromyographic (EMG) recordings in R(AB) transgenic mice that express a dominant negative form of the regulatory subunit of PKA in neurons within cortex and hippocampus. Previous studies have revealed that these mutant mice have reduced PKA activity that results in the impairment of hippocampus-dependent long-term memory and long-lasting forms of hippocampal synaptic plasticity.


METHODS
PKA assays, in situ hybridization, immunoblots, and sleep studies were performed in R(AB) transgenic mice and wild-type control mice.


RESULTS
We have found that R(AB) transgenic mice have reduced PKA activity within cortex and reduced Ser845 phosphorylation of the glutamate receptor subunit GluR1. R(AB) transgenic mice exhibit non-rapid eye movement (NREM) sleep fragmentation and increased amounts of rapid eye movement (REM) sleep relative to wild-type mice. Further, R(AB) transgenic mice have more delta power but less sigma power during NREM sleep relative to wild-type mice. After sleep deprivation, the amounts of NREM and REM sleep were comparable between wild-type and R(AB) transgenic mice. However, the homeostatic rebound of sigma power in R(AB) transgenic mice was reduced.


CONCLUSIONS
Alterations in cortical synaptic receptors, impairments in sleep continuity, and alterations in sleep oscillations in R(AB) mice imply that PKA is involved not only in synaptic plasticity and memory storage but also in the regulation of sleep/wake states.
Hellman
Kevin
K
Department of Neurobiology, University of Chicago, Chicago, IL, USA.
Hernandez
Pepe
P
Park
Alice
A
Abel
Ted
T
D000818:Animals; D001683:Biological Clocks / Q000235:genetics*; D002540:Cerebral Cortex / Q000502:physiology*; D002940:Circadian Rhythm / Q000235:genetics; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D004569:Electroencephalography; D004576:Electromyography; D005260:Female; D015870:Gene Expression / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000502:physiology; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000502:physiology; D018091:Receptors, AMPA / Q000235:genetics; D017981:Receptors, Neurotransmitter / Q000235:genetics; D012153:Retention, Psychology / Q000502:physiology; D012890:Sleep / Q000235:genetics*; D012892:Sleep Deprivation / Q000235:genetics; D012894:Sleep Stages / Q000235:genetics; D013788:Thalamus / Q000502:physiology*; D014851:Wakefulness / Q000235:genetics
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases; D018091:Receptors, AMPA; D017981:Receptors, Neurotransmitter