Sleep pattern and learning in knockdown mice with reduced cholinergic neurotransmission

Abstract

Impaired cholinergic neurotransmission can affect memory formation and influence sleep-wake cycles (SWC). In the present study, we describe the SWC in mice with a deficient vesicular acetylcholine transporter (VAChT) system, previously characterized as presenting reduced acetylcholine release and cognitive and behavioral dysfunctions. Continuous, chronic ECoG and EMG recordings were used to evaluate the SWC pattern during light and dark phases in VAChT knockdown heterozygous (VAChT-KDHET, n=7) and wild-type (WT, n=7) mice. SWC were evaluated for sleep efficiency, total amount and mean duration of slow-wave, intermediate and paradoxical sleep, as well as the number of awakenings from sleep. After recording SWC, contextual fear-conditioning tests were used as an acetylcholine-dependent learning paradigm. The results showed that sleep efficiency in VAChT-KDHET animals was similar to that of WT mice, but that the SWC was more fragmented. Fragmentation was characterized by an increase in the number of awakenings, mainly during intermediate sleep. VAChT-KDHET animals performed poorly in the contextual fear-conditioning paradigm (mean freezing time: 34.4±3.1 and 44.5±3.3 s for WT and VAChT-KDHET animals, respectively), which was followed by a 45% reduction in the number of paradoxical sleep episodes after the training session. Taken together, the results show that reduced cholinergic transmission led to sleep fragmentation and learning impairment. We discuss the results on the basis of cholinergic plasticity and its relevance to sleep homeostasis. We suggest that VAChT-KDHET mice could be a useful model to test cholinergic drugs used to treat sleep dysfunction in neurodegenerative disorders.

Effects of Sleep Deprivation on the Tryptophan Metabolism

“… 87 KYNA alters acetylcholine and glutamate which are critically involved in learning and memory, sleep dependent synaptic plasticity, and regulation of circadian rhythm. 90 - 93 Also, increased KYNA level restrains dopamine release into the synaptic cleft. 48 Elevated levels of KYNA in the brainstem, cortex, and hippocampus have been found to impair contextual memory and disrupt the sleep wake cycle in rodents.…”

Vesicular acetylcholine transporter defect underlies devastating congenital myasthenia syndrome

“…Acetylcholine is also an important neurotransmitter in the CNS, and reduced VAChT activity results in severe central as well as peripheral nervous system deficits, [28][29][30] consistent with the phenotype of our patients. Animal studies demonstrated cognitive and behavioral deficits with only 40%-50% decrease in VAChT expression, 27,[31][32][33] suggesting that central cholinergic synapses are even more sensitive to decreased VAChT activity than peripheral synapses, where symptoms appear only after 70% decrease in VAChT expression. 27 Notably, mutations in other genes reported to underlie CMS with presynaptic defects are also frequently associated with CNS manifestations.…”

Sleep–Wake Disorders in Alzheimer’s Disease: A Review

“…103 Rats showed low acetylcholine in the telencephalon after sleep deprivation for 96 h. 104 Mice with reduced cholinergic neurotransmission showed fragmentation of sleep and learning impairment. 105 In AD, the loss of synaptic and cholinergic neurons contributes to the progression of AD and accelerates the memory and attention deficits. 24 Acetylcholine works through metabotropic muscarinic receptors (mAChRs) or ionotropic nicotinic receptors (nAChRs).…”