Age-Related Decline in Circadian Output

Nakamura, Takahiro J.; Nakamura, Wataru; Yamazaki, Shin; Kudo, Takashi; Cutler, Tamara; Colwell, Christopher S.; Block, Gene D.

doi:10.1523/jneurosci.0451-11.2011

Cited by 332 publications

(287 citation statements)

References 35 publications

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“…This interpretation is consistent with the finding that TTX applied to hypothalamic slices blocks SCN action potentials but does not affect the circadian oscillation of clock genes (44), although longer-term TTX blockade may interfere with clock gene expression (7). Similarly, circadian clock gene expression does not seem to be impaired in animals with reduced delayed rectifier potassium currents (45) or aged animals (46), both of which show low-amplitude circadian rhythms. Finally, decreased amplitude of circadian locomotor activity could also result from the reduced Na V 1.1 channel activity in brain regions outside of the SCN.…”

Section: Discussionsupporting

confidence: 89%

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Han

Yu²,

Schwartz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Na V 1.1 is the primary voltage-gated Na + channel in several classes of GABAergic interneurons, and its reduced activity leads to reduced excitability and decreased GABAergic tone. Here, we show that Na V 1.1 channels are expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus. Mice carrying a heterozygous loss of function mutation in the Scn1a gene (Scn1a +/− ), which encodes the pore-forming α-subunit of the Na V 1.1 channel, have longer circadian period than WT mice and lack light-induced phase shifts. In contrast, Scn1a +/− mice have exaggerated light-induced negativemasking behavior and normal electroretinogram, suggesting an intact retina light response. Scn1a +/− mice show normal light induction of c-Fos and mPer1 mRNA in ventral SCN but impaired gene expression responses in dorsal SCN. Electrical stimulation of the optic chiasm elicits reduced calcium transients and impaired ventro-dorsal communication in SCN neurons from Scn1a +/− mice, and this communication is barely detectable in the homozygous gene KO (Scn1a −/− ). Enhancement of GABAergic transmission with tiagabine plus clonazepam partially rescues the effects of deletion of Na V 1.1 on circadian period and phase shifting. Our report demonstrates that a specific voltage-gated Na + channel and its associated impairment of SCN interneuronal communication lead to major deficits in the function of the master circadian pacemaker. Heterozygous loss of Na V 1.1 channels is the underlying cause for severe myoclonic epilepsy of infancy; the circadian deficits that we report may contribute to sleep disorders in severe myoclonic epilepsy of infancy patients. entrainment | neuronal oscillators | sodium channel T he mammalian suprachiasmatic nucleus (SCN) of the hypothalamus houses a master circadian clock that governs phase coordination between peripheral oscillators and overt circadian rhythms (1) as well as synchronization of these rhythms to the light-dark (LD) cycle through the retinohypothalamic tract (RHT) (2). Although SCN neurons are autonomous single-cell oscillators that rely on autoregulatory transcriptional/translational feedback loops of clock genes (3, 4), interneuronal synchronization is critical for the SCN to act as a tissue pacemaker with a coherent output (5, 6). Sodium-dependent action potentials are known to be essential for the synchronization between clock neurons in the SCN as well as necessary to maintain robust oscillations of clock gene expression (ref. 7 and reviewed in ref. 6), but the molecular identity of voltage-gated Na + channels contributing to the synchronization of the SCN neuronal network is currently unknown.Over 90% of SCN neurons contain GABA as a neurotransmitter and express GABA A and GABA B receptors (8-10), and electrophysiological and pharmacological studies in vitro have pointed to GABA as a key signal mediating SCN neuronal network properties (11,12). Studies of mutant mice show that voltage-gated sodium channel type 1 (Na V 1.1) encoded by the Scn1a gene is the primary voltage-gated Na + channel in...

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Section: Discussionsupporting

confidence: 89%

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Han

Yu²,

Schwartz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The reduction in amplitude corresponds with previous findings in SCN slices (Satinoff et al, 1993;Watanabe et al, 1995) and with recent in vivo recordings in the SCN of aged animals (Nakamura et al, 2011). Our present data show that a change in circadian phase coherence may underlie the amplitude reduction.…”

Section: Desynchronized Neuronal Activity Patternssupporting

confidence: 93%

Evidence for Neuronal Desynchrony in the Aged Suprachiasmatic Nucleus Clock

Farajnia¹,

Michel²,

Deboer³

et al. 2012

J. Neurosci.

201

212

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Aging is associated with a deterioration of daily (circadian) rhythms in physiology and behavior. Deficits in the function of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) have been implicated, but the responsible mechanisms have not been clearly delineated. In this report, we characterize the progression of rhythm deterioration in mice to 900 d of age. Longitudinal behavioral and sleep-wake recordings in up to 30-month-old mice showed strong fragmentation of rhythms, starting at the age of 700 d. Patch-clamp recordings in this age group revealed deficits in membrane properties and GABAergic postsynaptic current amplitude. A selective loss of circadian modulation of fast delayed-rectifier and A-type K ϩ currents was observed. At the tissue level, phase synchrony of SCN neurons was grossly disturbed, with some subpopulations peaking in anti-phase and a reduction in amplitude of the overall multiunit activity rhythm. We propose that aberrant SCN rhythmicity in old animals-with electrophysiological arrhythmia at the single-cell level and phase desynchronization at the network level-can account for defective circadian function with aging.

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“…Perhaps the most consistent changes observed in the aging SCN are related to the rhythm and synchrony of cell firing. Multiunit recordings in rodents indicate that the amplitude of SCN activity decreases with age, and that this decrease may reflect a loss of coherence in firing patterns across SCN cells in aged animals (115)(116)(117). Farajnia and colleagues (118) identified in aged mice (approximately 24 months) greater numbers of neurons within the SCN in which peak firing occurred out of phase with the dominant SCN rhythm in comparison with young mice (aged 3 months).…”

Section: Sensitivity To Zeitgebersmentioning

confidence: 99%

The aging clock: circadian rhythms and later life

Hood¹,

Amir²

2017

Journal of Clinical Investigation

388

322

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Age-Related Decline in Circadian Output

Cited by 332 publications

References 35 publications

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Evidence for Neuronal Desynchrony in the Aged Suprachiasmatic Nucleus Clock

The aging clock: circadian rhythms and later life

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Age-Related Decline in Circadian Output

Cited by 332 publications

References 35 publications

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Na V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Evidence for Neuronal Desynchrony in the Aged Suprachiasmatic Nucleus Clock

The aging clock: circadian rhythms and later life

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Product

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Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms

Na _V 1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms