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• W2090128879 abstract "Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of transient depolarizing currents and play a critical role in the electrical signaling between neurons. A null mutation in the VGSC gene SCN8A, which encodes the transmembrane protein Nav1.6, was identified previously in a human family. Heterozygous mutation carriers displayed a range of phenotypes, including ataxia, cognitive deficits, and emotional instability. A possible role for SCN8A was also proposed in studies examining the genetic basis of attempted suicide and bipolar disorder. In addition, mice with a Scn8a loss-of-function mutation (Scn8amed-Tg/+) show altered anxiety and depression-like phenotypes. Because psychiatric abnormalities are often associated with altered sleep and hormonal patterns, we evaluated heterozygous Scn8amed-jo/+ mutants for alterations in sleep-wake architecture, diurnal corticosterone levels, and behavior. Compared with their wild-type littermates, Scn8amed-jo/+ mutants experience more non-rapid eye movement (non-REM) sleep, a chronic impairment of REM sleep generation and quantity, and a lowered and flattened diurnal rhythm of corticosterone levels. No robust differences were observed between mutants and wild-type littermates in locomotor activity or in behavioral paradigms that evaluate anxiety or depression-like phenotypes; however, Scn8amed-jo/+ mutants did show enhanced spatial memory. This study extends the spectrum of phenotypes associated with mutations in Scn8a and suggests a novel role for altered sodium channel function in human sleep disorders. Voltage-gated sodium channels (VGSCs) are responsible for the initiation and propagation of transient depolarizing currents and play a critical role in the electrical signaling between neurons. A null mutation in the VGSC gene SCN8A, which encodes the transmembrane protein Nav1.6, was identified previously in a human family. Heterozygous mutation carriers displayed a range of phenotypes, including ataxia, cognitive deficits, and emotional instability. A possible role for SCN8A was also proposed in studies examining the genetic basis of attempted suicide and bipolar disorder. In addition, mice with a Scn8a loss-of-function mutation (Scn8amed-Tg/+) show altered anxiety and depression-like phenotypes. Because psychiatric abnormalities are often associated with altered sleep and hormonal patterns, we evaluated heterozygous Scn8amed-jo/+ mutants for alterations in sleep-wake architecture, diurnal corticosterone levels, and behavior. Compared with their wild-type littermates, Scn8amed-jo/+ mutants experience more non-rapid eye movement (non-REM) sleep, a chronic impairment of REM sleep generation and quantity, and a lowered and flattened diurnal rhythm of corticosterone levels. No robust differences were observed between mutants and wild-type littermates in locomotor activity or in behavioral paradigms that evaluate anxiety or depression-like phenotypes; however, Scn8amed-jo/+ mutants did show enhanced spatial memory. This study extends the spectrum of phenotypes associated with mutations in Scn8a and suggests a novel role for altered sodium channel function in human sleep disorders. The mammalian genome contains four voltage-gated sodium channel (VGSC) 4The abbreviations used are: VGSCvoltage-gated sodium channelCNScentral nervous systemWTwild typeHPAhypothalamic-pituitary-adrenalREMrapid eye movementNREMnon-REMECoGeletrocorticogramEMGelectromyographySDsleep deprivationrANOVArepeated measures analysis of varianceCORTcorticosteroneTTXtetrodotoxin. α-subunit genes that are highly expressed in the central nervous system (CNS), SCN1A, SCN2A, SCN3A, and SCN8A, which encode the transmembrane proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively. VGSCs play a critical role in the initiation and propagation of transient depolarizing currents and electrical signaling between cells. Nav1.6, the most abundantly expressed VGSC in the CNS, is localized in somata and dendrites of projection neurons, nodes of Ranvier of both peripheral and CNS neurons, and axonal initial segments (1Caldwell J.H. Schaller K.L. Lasher R.S. Peles E. Levinson S.R. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 5616-5620Crossref PubMed Scopus (527) Google Scholar, 2Boiko T. Rasband M.N. Levinson S.R. Caldwell J.H. Mandel G. Trimmer J.S. Matthews G. Neuron. 2001; 30: 91-104Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 3Boiko T. Van Wart A. Caldwell J.H. Levinson S.R. Trimmer J.S. Matthews G. J. Neurosci. 2003; 23: 2306-2313Crossref PubMed Google Scholar). Nav1.6 channels are expressed in a wide variety of cells, including Purkinje cells, motor neurons in the brain stem and spinal cord, pyramidal and granule neurons in the hippocampus and cortex, and glial cells and Schwann cells (4Chen Y. Yu F.H. Sharp E.M. Beacham D. Scheuer T. Catterall W.A. Mol. Cell Neurosci. 2008; 38: 607-615Crossref PubMed Scopus (89) Google Scholar). Nav1.6 channels are responsible for a large portion of the persistent sodium current and display several unique biophysical properties that contribute to a propensity for sustained repetitive firing (4Chen Y. Yu F.H. Sharp E.M. Beacham D. Scheuer T. Catterall W.A. Mol. Cell Neurosci. 2008; 38: 607-615Crossref PubMed Scopus (89) Google Scholar). voltage-gated sodium channel central nervous system wild type hypothalamic-pituitary-adrenal rapid eye movement non-REM eletrocorticogram electromyography sleep deprivation repeated measures analysis of variance corticosterone tetrodotoxin. A broad effect of Scn8a dysfunction on neuronal excitability has been observed in mice with different Scn8a mutations. The Scn8amed-jo mutation, a threonine-to-alanine substitution in the S4–S5 linker of domain III, causes a 10-mV positive shift in the voltage dependence of activation in Purkinje cells (5Smith M.R. Goldin A.L. Neuroreport. 1999; 10: 3027-3031Crossref PubMed Scopus (16) Google Scholar) and also reduces the resurgent sodium current (6Raman I.M. Sprunger L.K. Meisler M.H. Bean B.P. Neuron. 1997; 19: 881-891Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar), diminishing the repetitive firing of the Purkinje cells. Reduced transient and persistent sodium current was seen in pyramidal cells of the prefrontal cortex, a site of executive function, in heterozygous Scn8a null mutants (7Maurice N. Tkatch T. Meisler M. Sprunger L.K. Surmeier D.J. J. Neurosci. 2001; 21: 2268-2277Crossref PubMed Google Scholar). Lower sustained and instantaneous firing rates in the initial segment of retinal ganglion cells were also found in heterozygous null mutants (8Van Wart A. Matthews G. J. Neurosci. 2006; 26: 7172-7180Crossref PubMed Scopus (102) Google Scholar). Mice with Scn8a mutations display a variety of recessive movement phenotypes. Homozygous Scn8amed mice that carry a loss-of-function mutation exhibit muscle weakness, progressive paralysis, and death by 3–4 weeks after birth (9Burgess D.L. Kohrman D.C. Galt J. Plummer N.W. Jones J.M. Spear B. Meisler M.H. Nat. Genet. 1995; 10: 461-465Crossref PubMed Scopus (253) Google Scholar). Homozygous Scn8amed-jo/+ mutants have a less severe phenotype (10Kohrman D.C. Smith M.R. Goldin A.L. Harris J. Meisler M.H. J. Neurosci. 1996; 16: 5993-5999Crossref PubMed Google Scholar); by 3 weeks of age, these mutants show an unsteady, wide-based gait and rhythmic tremor of the head and neck during movement (11Meisler M.H. Kearney J. Escayg A. MacDonald B.T. Sprunger L.K. Neuroscientist. 2001; 7: 136-145Crossref PubMed Scopus (52) Google Scholar). However, unlike homozygous null mutants, the Scn8amed-jo homozygous mutants often have a normal life span (11Meisler M.H. Kearney J. Escayg A. MacDonald B.T. Sprunger L.K. Neuroscientist. 2001; 7: 136-145Crossref PubMed Scopus (52) Google Scholar). Closer examination of heterozygous Scn8a mutants has begun to reveal a number of dominant phenotypes. For instance, heterozygous Scn8amed-Tg mice with a loss-of-function mutation display greater avoidance of the center zone during open field exploration, an increased tendency to remain on the dark side of a light/dark box, and increased immobility in the forced swim test compared with wild-type (WT) littermates (12McKinney B.C. Chow C.Y. Meisler M.H. Murphy G.G. Genes Brain Behav. 2008; 7: 629-638Crossref PubMed Scopus (41) Google Scholar). These observations suggest that reduced Scn8a expression may be associated with increased anxiety and pronounced stress-induced coping strategies (12McKinney B.C. Chow C.Y. Meisler M.H. Murphy G.G. Genes Brain Behav. 2008; 7: 629-638Crossref PubMed Scopus (41) Google Scholar). We have found that heterozygous Scn8amed and Scn8amed-jo mutants are more resistant to seizures induced by the chemical convulsants flurothyl and kainic acid compared with WT littermates (13Martin M.S. Tang B. Papale L.A. Yu F.H. Catterall W.A. Escayg A. Hum. Mol. Genet. 2007; 16: 2892-2899Crossref PubMed Scopus (153) Google Scholar). In contrast, we also observed that heterozygous Scn8amed, Scn8amed-jo, and Scn8a8J mutants display spontaneous spike wave discharges, the hallmark of absence seizures (14Papale L.A. Beyer B. Jones J.M. Sharkey L.M. Tufik S. Epstein M. Letts V.A. Meisler M.H. Frankel W.N. Escayg A. Hum. Mol. Genet. 2009; 18: 1633-1641Crossref PubMed Scopus (88) Google Scholar). Heterozygous Scn8amed-Tg mutants are also more resistant to electrical kindling (15Blumenfeld H. Lampert A. Klein J.P. Mission J. Chen M.C. Rivera M. Dib-Hajj S. Brennan A.R. Hains B.C. Waxman S.G. Epilepsia. 2009; 50: 44-55Crossref PubMed Scopus (101) Google Scholar). A null mutation in the human SCN8A gene has been reported in a small pedigree in which heterozygous mutation carriers exhibited a range of phenotypes, including ataxia, cognitive deficits, and emotional instability (16Trudeau M.M. Dalton J.C. Day J.W. Ranum L.P. Meisler M.H. J. Med. Genet. 2006; 43: 527-530Crossref PubMed Scopus (136) Google Scholar). A possible role for SCN8A was also reported in studies examining the genetic basis of attempted suicide (17Wasserman D. Geijer T. Rozanov V. Wasserman J. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 2005; 133B: 116-119Crossref PubMed Scopus (46) Google Scholar) as well as bipolar disorder (18Wang Y. Zhang J. Li X. Ji J. Yang F. Wan C. Feng G. Wan P. He L. He G. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2008; 32: 1902-1904Crossref PubMed Scopus (11) Google Scholar). These findings suggest that SCN8A dysfunction may contribute to a variety of neurological and neuropsychiatric disorders. Neurobiological investigations of psychiatric disorders, particularly those involving alterations in anxiety and depression, often take the sleep-wake cycle into consideration. Moreover, disrupted sleep is a key feature of depression, schizophrenia, mental retardation, dementia, and post-traumatic stress disorder (19Bourgeois J.A. Coffey S.M. Rivera S.M. Hessl D. Gane L.W. Tassone F. Greco C. Finucane B. Nelson L. Berry-Kravis E. Grigsby J. Hagerman P.J. Hagerman R.J. J. Clin. Psychiatry. 2009; 70: 852-862Crossref PubMed Scopus (162) Google Scholar, 20Young A.H. Stress. 2004; 7: 205-208Crossref PubMed Scopus (72) Google Scholar, 21de Kloet C.S. Vermetten E. Geuze E. Kavelaars A. Heijnen C.J. Westenberg H.G. J. Psychiatr. Res. 2006; 40: 550-567Crossref PubMed Scopus (361) Google Scholar, 22Walker E. Mittal V. Tessner K. Annu. Rev. Clin. Psychol. 2008; 4: 189-216Crossref PubMed Scopus (433) Google Scholar). To better understand the full range of phenotypes associated with altered Scn8a function, we characterized the sleep-wake architecture and behavioral responses of Scn8amed-jo/+ mutants. Because the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays a major role in psychiatric diseases, we also evaluated Scn8amed-jo/+ mutants for alterations in the circadian variation of corticosterone secretion. We found a robust impairment in the generation and maintenance of rapid eye movement (REM) sleep, an increase in non-REM (NREM) sleep, a lowered and flattened diurnal rhythm of corticosterone secretion indicating hypofunctioning of the HPA axis, and a modest improvement in spatial memory. Male Scn8amed-jo/+ mutants were purchased from The Jackson Laboratories (Bar Harbor, ME) and maintained on the C57BL/6J background. The mice were housed in ventilated cages under uniform conditions in a pathogen-free mouse facility with a 12-h light/dark cycle. Food and water were available ad libitum. All experiments were approved by the Emory University Institutional Animal Care and Use Committee. Genotyping of Scn8amed-jo/+ mutants was performed using primer pair 8aF (5′-ATGCCACAGAAGTGTCATTCC) and 8aR (5′-GGTATTTCCCAGCAAACAGGT) (10Kohrman D.C. Smith M.R. Goldin A.L. Harris J. Meisler M.H. J. Neurosci. 1996; 16: 5993-5999Crossref PubMed Google Scholar). PCR amplification was performed with one cycle at 94 °C for 2 min and 40 cycles of 94 °C for 30 s, 55 °C for 30 s, and 72 °C for 1 min. The 213-bp PCR product was digested with MslI to produce fragments of 129, 75, and 9 bp from the wild-type allele and 102, 75, 27, and 9 bp from the mutant allele. Under isoflurane anesthesia, 10 male Scn8amed-jo/+ mutants and 9 male WT littermates (3–4 months old) were surgically implanted with ECoG and electromyography (EMG) electrodes for polysomnographic recordings. The implant consisted of four sterile screw electrodes (Vintage Machine Supplies, Medina, OH) that were placed subdurally. Two screws were placed on the right hemisphere (2 mm anterior-posterior (AP) and 1.2 mm lateral to the midline (LM); 1.5 mm AP and 1.2 mm LM). On the left hemisphere, the two other screw placements were 0.5 mm AP and 2.2 LM and 3.5 mm AP and 2.2 mm LM. Fine wire electrodes were inserted into the left and right neck muscles for EMG acquisition. Postsurgical pain management was achieved with the administration of ibuprofen (0.1 mg/kg) in the drinking water for 3 days. After the surgery, the animals were housed in Plexiglas boxes (20 × 20 × 30 cm) and allowed to recover for 14 days. The animals were then connected to the ECoG cable and, following 48 h of habituation, 48 h of continuous ECoG/EMG data were collected. Amplified ECoG and EMG signals were digitally acquired, collected, and processed by the Somnologica sleep-recording software package (Embla Medical, Reykjavik, Iceland). The amount of time spent in each state of vigilance was obtained from 48 h of continuous ECoG base-line sleep recordings and manually scored in 10-s intervals. The time spent in each state of vigilance during the 12-h light and 12-h dark phases from day 1 and day 2 were averaged. To further examine the circadian variation, the average time spent in each state of vigilance during the light and dark phases was also examined in 2-h intervals. The waveforms were classified for wakefulness, NREM sleep, and REM sleep. A low voltage, high frequency ECoG with elevated and variable EMG was defined as wakefulness. NREM sleep was characterized by an ECoG signal that increased in amplitude and decreased in frequency, with the clear presence of high amplitude delta waves (0.5–4 Hz) and an EMG signal that displayed low regular muscular tone. REM sleep was identified by the presence of regular theta waves (4.5–8 Hz) with a lack of muscle tone and phasic bursts of varying duration and amplitude. For power spectral analysis, all 10-s intervals of NREM sleep were subjected to fast Fourier transformation. The power density in the delta frequency (0.5–4 Hz) was determined by the average for each group. Following the 48 h of base-line ECoG/EMG recordings, Scn8amed-jo/+ mutants and WT littermates were sleep-deprived during the first 6 h of the light phase (7 a.m. to 1 p.m.). Sleep deprivation (SD) was carried out by the introduction of objects into the cage and tapping the cages whenever the animals appeared drowsy. The animals were not touched during SD and were never disturbed during feeding or drinking. SD was immediately followed by 18 h of continuous ECoG recordings during the recovery period (6-h light phase, 12-h dark phase). Blood was collected from the facial vein of 10 male Scn8amed-jo/+ mutants and 10 male WT littermates into Microvette CB 300 EDTA tubes (Starstedt) within 5 min of disturbing the cage at either 7 a.m. or 7 p.m. in order to coincide with the expected nadir and peak of circulating corticosterone levels. The 7 a.m. and 7 p.m. samples from each mouse were collected on consecutive days. Plasma was separated by centrifugation at 7000 rpm for 10 min at 4 °C and stored at −20 °C. Plasma corticosterone levels were assayed using a commercial RIA kit (MP Biomedicals) according to the manufacturer's instructions. Ten male Scn8amed-jo/+ mutants and 10 male WT littermates (3–6 months old) were group-housed and maintained on a 12-h light/dark cycle (lights on at 7 a.m.). All testing was performed during the light phase between 10 a.m. and 2 p.m., and a period of 1 week was allowed between tests. The same group of animals was subjected to the following sequence of behavioral tests: locomotor activity, light/dark box, open field, elevated plus maze, forced swim, and object recognition. An experimenter who was blind to the animal's genotype scored videotaped recordings of each test. The animals were individually placed in unfamiliar transparent Plexiglas chambers (40 × 20 × 20 cm). Each chamber was placed on a rack containing seven infrared photobeams spaced 5 cm apart, with each beam 5 cm from the cage wall (San Diego Instruments Inc., La Jolla, CA). Ambulatory activity (consecutive beam brakes) was continuously recorded for 50 h (first 2 h, exploratory activity in response to the novel environment; remaining 48 h, endogenous circadian rhythm). The light/dark box test was performed in a rectangular box that was divided to form a light and a dark compartment. The walls of the light compartment (20 × 14 × 14.5 cm) were covered with white paper. The walls of the dark compartment (10 × 14 × 14.5 cm) were covered with black paper and had a roof constructed of black paper. A removable cardboard partition containing a small square opening at floor level (5 × 5 cm) was used to divide the box into light and dark sides. Each animal was placed into the light side of the box, facing away from the dark side and allowed to explore the apparatus for 5 min. The measurements scored were as follows: time spent in the light and dark sides, latency to enter the dark side, and the number of transitions between each side. The open field apparatus consisted of a circular arena (96.5-cm diameter) with opaque Plexiglas walls (28 cm high). A marker was used to inscribe a smaller circle 18 cm from the walls. Each mouse was placed in the inner circle of the apparatus and allowed to explore for 5 min. The times spent in the inner and outer circles were scored. The elevated plus maze consisted of two open and two closed arms elevated 76 cm above the floor, with each arm projecting 30.5 cm from the center (5 × 5 cm). Each mouse was individually placed in the central area and allowed to explore for 5 min. The measurements scored were as follows: time spent in closed arms, time spent in open arms, and number of entries into open and closed arms. The mice were individually placed into a Plexiglas cylinder (10-cm internal diameter, 50 cm high) filled with water (10-cm deep, 25–26 °C) for 6 min. During the last 4 min of the test, the time spent floating was scored. Floating was defined as immobility or minimal movements necessary to maintain the head above the water. Testing was conducted in an open field box (60 × 60 × 47 cm) constructed of Plexiglas and painted white. In total, four colored ornamental objects were used for testing: a bear, an elephant, a closed bottle, and a dog. The objects were similar in size (∼10 × 6 × 6 cm) but differed in texture. Prior to the test session, the mice were each placed in the empty open field for 5 min on 5 consecutive days (habituation period). The test session consisted of three successive trials, each 5 min in duration, separated by a 20-min intertrial interval. After completing each trial, the animal was returned to the home cage, and the apparatus and objects were wiped with 70% alcohol. In trial 1, the mouse was placed in the empty open field and allowed to freely explore the testing arena. For trial 2, three objects were introduced into the open field, each placed in a separate corner ∼5 cm from the walls. The selection of the objects and their placement within the open field was randomized for each pair of mice. The mice were paired so that one mutant and one WT littermate were examined using the same layout of the objects. Each mouse was placed in the center of the box, facing the unoccupied corner, and the time spent exploring each object was recorded. For trial 3, one object was maintained in the same position as in trial 2 (repeated object), one object from trial 2 was replaced with a novel object in the same location (novel object), and one object from trial 2 was relocated to the previously unoccupied corner of the open field (relocated object). The time spent exploring each object during the 5-min trial was recorded. A mouse was considered to be exploring an object when it was facing the object at a close distance (≤5 mm) or when the mouse's nose or front paws were in contact with the object. The data were reported as means ± S.E. Homogeneity of variance was assessed by the Levene test and normal distribution of the data by the Shapiro-Wilk test. For sleep analysis, two-way repeated measures analysis of variance (rANOVA) was used to detect differences between genotypes (mutant versus WT) when the light and dark phases were examined in 12-h periods as well as for each 2-h interval. rANOVA was also used to detect differences within genotypes (base line versus recovery following sleep deprivation) during light and dark phases. Post hoc analysis was performed by Tukey's test. For all the behavior tests except the object recognition test, two-tailed t-tests were used to detect differences between genotypes with significance set at p < 0.05. For the object recognition test, a one-tailed t test was used to analyze differences between genotypes. A value of 50% represented chance performance. Therefore, the one-tailed t test showed whether the performance of each genotype was above 50%. Base-line sleep and circadian rhythm dynamics in Scn8amed-jo/+ mutants were compared with WT littermates. Diurnal rhythms for each state of vigilance (wakefulness, NREM sleep, and REM sleep) were present in both genotypes, with expected overall increases in sleep amount during the light phase and increases in wake amount and locomotor activity during the dark phase (Fig. 1). However, sleep and wake amounts and distribution in the mutants differed from WT littermates. The amount of wakefulness observed in mutants and WT littermates was comparable during the light phase. However, the mutants experienced 12% less wakefulness during the dark phase (Fig. 1A). rANOVA detected effects of group (F(1,17) = 9.48, p < 0.01) and time (F(1,17) = 369.9, p < 0.0001). Post hoc analysis indicated that the decreased amount of wakefulness during the dark phase was statistically significant (p < 0.01, Tukey's test; Fig. 1A). Although wake amounts during the light phase were not statistically different between genotypes, the mutants did exhibit 14% more NREM sleep during the light phase and 35% more NREM sleep during the dark phase (Fig. 1C). rANOVA detected effects of group (F(1,17) = 23.8, p < 0.0001) and time (F(1,17) = 377.6, p < 0.0001). Post hoc analysis revealed that the amounts of NREM sleep observed in the mutants during the light and dark phases were statistically different from corresponding periods in the WT littermates (light, p < 0.05; dark, p < 0.01, Tukey's test). In contrast to the increased amount of NREM sleep, the mutants experienced 55% less REM sleep during the light phase when compared with the WT littermates (Fig. 1E). Surprisingly, during the dark phase, the percentage of time spent in REM sleep was similar between genotypes. rANOVA detected effects of group (F(1,17) = 59.8, p < 0.0001), time (F(1,17) = 205.2, p < 0.0001), and an interaction between group and time (F(1,17) = 47.3, p < 0.0001). The impairment of REM sleep amount in the mutants during the light phase was statistically significant (p < 0.0001, Tukey's test). To perform a more detailed sleep-wake analysis, the different states of vigilance were also analyzed in 2-h intervals. rANOVA followed by post hoc analysis did not reveal any statistically significant differences between genotypes in amounts of wake (Fig. 1B) and NREM sleep (Fig. 1D) during the light and dark phases (p > 0.05 for all comparisons, Tukey's test). In contrast, the mutants spent less time in REM sleep during the last 8 h (11 a.m. to 7 p.m.) of the light period (Fig. 1F). rANOVA detected effects of group (F(1,17) = 90.4, p < 0.001) and time (F(5,85) = 5.8, p < 0.001). The amount of REM sleep was statistically different between genotypes during this period (p < 0.01, Tukey's test). However, differences in amount of REM sleep during the dark phase were not statistically significant (p > 0.05, Tukey's test; Fig. 1F). Because no compensatory increase in REM sleep was observed during the dark phase, the mutants appear to be chronically REM sleep-deprived. Representative examples of ECoG waveforms for each state of vigilance are shown in supplemental Fig. 1. To determine whether the mutants have altered sleep-wake cycling, we analyzed the number of transitions (stage shifts) between the different states of vigilance and the mean duration of REM sleep bouts (Table 1). For the stage shifts during the light period, the mutants had fewer transitions from NREM sleep to REM sleep and from REM sleep to wakefulness when compared with WT littermates. rANOVA detected effects of group (F(1,17) = 20.2, p < 0.001), shifts (F(4,68) = 255.07, p < 0.0001), and interaction between group and shifts (F(4,68) = 17.1, p < 0.0001). These differences in the number transitions were statistically significant (p < 0.01 for both comparisons, Tukey's test). No statistically significant differences in stage shifts were observed during the dark phase. The diminished number of transitions between NREM and REM sleep in the mutants contributed to the reduced amount of REM sleep during the light phase.TABLE 1Number of arousals and sleep-wake transitions in Scn8amed-jo/+ mutants and WT littermates during the 24-h base-line recording12-h light phase12-h dark phaseScn8amed-jo/+WTScn8amed-jo/+WTTotal arousals105.9 ± 11.3132.7 ± 7.663.2 ± 5.264.5 ± 7.2Wake to NREM79.6 ± 4.597.4 ± 3.848.5 ± 4.242.9 ± 4.9NREM to wake53.5 ± 3.744.7 ± 437.4 ± 3.630.6 ± 4.4NREM to REM33.8 ± 2.3ap < 0.01, rANOVA followed by Tukey's post hoc test for the stage shift and unpaired Student's t test for REM duration.59.3 ± 3.312.7 ± 1.112.9 ± 1.7REM to NREM7.7 ± 1.76.8 ± 2.22.2 ± 0.50.9 ± 0.2REM to wake26.1 ± 1.9ap < 0.01, rANOVA followed by Tukey's post hoc test for the stage shift and unpaired Student's t test for REM duration.52.6 ± 1.810.5 ± 1.212 ± 1.6REM duration (min)0.93 ± 0.13ap < 0.01, rANOVA followed by Tukey's post hoc test for the stage shift and unpaired Student's t test for REM duration.1.17 ± 0.181.01 ± 0.221.12 ± 0.15a p < 0.01, rANOVA followed by Tukey's post hoc test for the stage shift and unpaired Student's t test for REM duration. Open table in a new tab The average length of each episode of REM sleep was obtained by dividing the total duration of REM sleep by the total number of REM sleep episodes. When compared with WT littermates, REM sleep duration was statistically lower in the mutants during the light phase (Scn8amed-jo/+, 0.93 ± 0.13 min; WT, 1.17 ± 0.18 min; t(17) = 3.11, p < 0.01). However, REM sleep duration was comparable during the dark phase (Scn8amed-jo/+, 1.01 ± 0.2 min; WT, 1.12 ± 0.15 min; t(17) = 1.18, p > 0.05). Therefore, the decrease in overall REM sleep observed during base-line recording is due to a reduction in both the number and duration of REM sleep episodes in the mutants during the light phase. NREM sleep is a restorative phase of sleep that is characterized by slow wave delta oscillations (0.5–4 Hz). The strength of these oscillations, measured as delta power, is positively associated with the duration of prior wakefulness. Consequently, delta power is a quantitative measure of sleep intensity during NREM sleep. Because we observed that Scn8amed-jo/+ mutants are chronically REM sleep-deprived and experience excessive NREM sleep, we sought to determine whether sleep intensity was also altered. Because absolute values of delta power vary substantially between subjects, we performed a within-subject normalization of delta power to allow comparisons between mutants and WT littermates. We accomplished this by averaging the absolute delta power into 2-h intervals for each subject and dividing each 2-h average by the 24-h average (supplemental Fig. 2). rANOVA followed by post hoc analysis did not reveal any statistically significant differences between mutants and WT littermates (p > 0.05, Tukey's test). We also compared sleep-wake amounts between mutants and WT littermates following a period of SD. After 6 h of SD, continuous ECoG recordings were obtained for 18 h of the subsequent recovery period (6-h light phase, 12-h dark phase). Because the base-line sleep distribution was different between the two genotypes, analyses were performed within each genotype. The amount of NREM and REM sleep during the recovery period was compared with the equivalent time period during base-line recording. Although 6 h of SD is considered to be mild, increased levels of NREM and REM sleep were expected during the recovery period. The percentage increase in NREM sleep in" @default.
• W2090128879 created "2016-06-24" @default.
• W2090128879 creator A5005938180 @default.
• W2090128879 creator A5016795108 @default.
• W2090128879 creator A5019081879 @default.
• W2090128879 creator A5077819675 @default.
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• W2090128879 date "2010-05-01" @default.
• W2090128879 modified "2023-10-15" @default.
• W2090128879 title "Dysfunction of the Scn8a Voltage-gated Sodium Channel Alters Sleep Architecture, Reduces Diurnal Corticosterone Levels, and Enhances Spatial Memory" @default.
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