Photic Entrainment Is Altered in the 5-HT_1B Receptor Knockout Mouse

Abstract

The hypothalamic suprachiasmatic nucleus (SCN) is a circadian oscillator that receives glutamatergic afferents from the retina and serotonergic afferents from the midbrain. Activation of presynaptic serotonin 1B (5-HT1B) receptors on retinal terminals in the SCN inhibits retinohypothalamic neurotransmission and light-induced behavioral phase shifts. To assess the role of 5-HT1B receptors in photic entrainment, 5-HT1B receptor knockout (5-HT1B KO) and wild-type (WT) mice were maintained in non-24 h L:D cycles (T cycles). WT mice entrained to T = 21 h and T = 22 h cycles, whereas 5-HT1B KO animals did not. 5-HT1B KO animals did entrain to T = 23 h and T = 26 h cycles, although their phase angle of entrainment was altered compared to WT animals. 5-HT1BKO mice were significantly more phase delayed under T = 23 h conditions and significantly more phase advanced under T = 26 h conditions compared to WT mice. When 5-HT1B KO mice were housed in a T = 23 h short-day photoperiod (9.5L:13.5D), the delayed phase angle of entrainment was more pronounced. Light-induced phase shifts were reduced in 5-HT1B KO mice, consistent with their behavior in T cycles, suggesting an attenuated response to light. Based on previous work, this attenuated response to light might not have been predicted but can be explained by consideration of GABAergic mechanisms within the SCN. Phase-delayed circadian rhythms during the short days of winter are characteristic of patients suffering from seasonal affective disorder, and 5-HT has been implicated in its pathophysiology. The 5-HT1B KO mouse may be useful for investigating the altered entrainment evident during this serious mood disorder.

Presynaptic GABABReceptors Regulate Retinohypothalamic Tract Synaptic Transmission by Inhibiting Voltage-Gated Ca2+Channels

“…The GABA B and 5-HT systems may overlap in their regulation of photic input to the circadian system. Presynaptic 5-HT 1B receptors inhibit GABA release in the SCN that may contribute to the tonic GABA B -receptormediated inhibition (Bramley et al 2005;Gannon et al 1995;Sollars et al 2006). 5-HT 1B -knockout mice have smaller lightinduced phase shifts than would be predicted, possibly arising from disinhibition of GABA B signaling by removal of 5-HT inhibition of GABA release (Sollars et al 2006).…”

Clinical Advances of Recent Discoveries about the Interaction between Circadian and Serotoninergic Systems

“…In this sense, genetic alterations in the network of 5-HT genes have demonstrated a significant influence on the circadian behavior . Mice with deletion in the 5-HT1B receptor gene, which is located on the presynaptic terminals of retinal ganglion cells that project to the SCN, exhibit a pattern of reduction of adaptability of endogenous rhythms promoted by light (Sollars, Ogilvie, Simpson, & Pickard, 2006). Such data cooperate the discovery that agonist of this receptor can promote deviations in the important role of light in the circadian regulation (Pickard & Rea, 1997).…”

Intrinsically photosensitive retinal ganglion cells

“…One site of serotonin's action in the SCN is at 5-HT 1B receptors on ipRGC terminals; activation of these presynaptic inhibitory receptors modulates the response of the SCN to photic input (Pickard et al 1996(Pickard et al , 1999. Moreover, 5-HT 1B receptor knockout mice maintained under short-day (winterlike) conditions exhibit a delayed phase relationship to the day/night cycle (Sollars et al 2006) resembling the phase delay demonstrated by people suffering from recurrent winter depression or seasonal affective disorder (SAD) (Lewy et al 1987;Terman and Terman 2005). Recently Provencio and colleagues described a missense variant of the melanopsin gene in SAD patients (Roecklein et al 2009).…”

“…Recently Provencio and colleagues described a missense variant of the melanopsin gene in SAD patients (Roecklein et al 2009). It is likely that many factors contribute to the etiology of SAD, and these may well include reduced sensitivity to light that may result from abnormalities in phototransduction in ipRGCs (Roecklein et al 2009) and/or abnormalities in 5-HT neurotransmission in the SCN (Sollars et al 2006).…”

“…Recently Provencio and colleagues described a missense variant of the melanopsin gene in SAD patients (Roecklein et al 2009). It is likely that many factors contribute to the etiology of SAD, and these may well include reduced sensitivity to light that may result from abnormalities in phototransduction in ipRGCs (Roecklein et al 2009) and/or abnormalities in 5-HT neurotransmission in the SCN (Sollars et al 2006).Alterations in the phase angle of entrainment to the day/night cycle are associated with alterations in the amplitude of the diurnal rhythm of plasma corticosterone secreted from the adrenal cortex; a blunted cortisol rhythm has been reported in SAD patients (Avery et al 1997). The reduction in corticosterone secretion may result from an altered phase relationship between the adrenal gland's innate circadian rhythm in steroid biosynthesis to the day/night cycle (Oster et al 2006;Son et al 2008).…”