Regulating Wakefulness: GABAergic Inhibition of Histaminergic Neurons

We take sleeping for granted, spending about a third of our lives asleep, but it is estimated around a quarter of people suffer from extreme tiredness caused by sleep disorders. Sleep disorders can make switching from a wake state to a sleep state, or vice versa, difficult. Researchers at Imperial College London are looking into the mechanisms behind the sleep-wake switch. Their paper "GABAergic Inhibition of Histaminergic Neurons Regulates Active Waking But Not the Sleep–Wake Switch or Propofol-Induced Loss of Consciousness" details some of their findings.

The tuberomamillary nucleus (TMN) is the major waking system in the brain containing histaminergic neurons active only during waking and not in sleep. Sleep-active inhibitory GABAergic neurons innervate the waking neurons. The interaction was thought to inhibit wakefulness and promote sleep as part of the "flip-flop" model of the sleep-wake switch. However, research from Imperial College has thrown into question the necessity of the GABAergic neurons for switching to the sleep state.

Researchers discovered that removing GABA receptors from TMN histaminergic neurons caused these neurons to have a lower threshold potential and produce more action potentials. However, this cellular change did not affect the animals' sleep/wake cycle, or EEG recordings.

In addition, the hyperpolarising effect of the sedative propofol on TMN neurons was abolished in animals with GABA receptors removed. Despite this lack of reaction to propofol in histaminergic neurons the behavioural reaction to injections of propofol was unchanged. These results led to the conclusion that the TMN histaminergic neurons are not responsible for the regulation of the sleep-wake switch or the action of propofol.

Researchers did find that when mice lacking GABAA receptors were placed in a highly stimulating environment they remained in a high state of wakefulness much longer than controls. Therefore, suggesting that fast synaptic GABAergic inhibition is important for regulating active waking and arousal states.

So, although turning down our histaminergic neurons may not help us get to sleep at night, they might help us get over our exciting, challenging or even upsetting day. Understanding these mechanisms could be the first step in helping people who suffer from sleep disorders such as insomnia or narcolepsy.