Abstract
Up-/down-state transitions are a form of network activity observed when sensory input into the cortex is diminished such as during non-REM sleep. Up-states emerge from coordinated signaling between glutamatergic and GABAergic synapses and are modulated by systems that affect the balance between inhibition and excitation. We hypothesized that the endocannabinoid (EC) system, a neuromodulatory system intrinsic to the cortical microcircuitry, is an important regulator of up-states and sleep. To test this hypothesis, up-states were recorded from layer V/VI pyramidal neurons in organotypic cultures of wild-type or CB1R knockout (KO) mouse prefrontal cortex. Activation of the cannabinoid 1 receptor (CB1) with exogenous agonists or by blocking metabolism of endocannabinoids, anandamide or 2-arachidonoyl glycerol, increased up-state amplitude and facilitated action potential discharge during up-states. The CB1 agonist also produced a layer II/III-selective reduction in synaptic GABAergic signaling that may underlie its effects on up-state amplitude and spiking. Application of CB1 antagonists revealed that an endogenous EC tone regulates up-state duration. Paradoxically, the duration of up-states in CB1 KO cultures was increased suggesting that chronic absence of EC signaling alters cortical activity. Consistent with increased cortical excitability, CB1 KO mice exhibited increased wakefulness as a result of reduced NREM sleep and NREM bout duration. Under baseline conditions, NREM delta (0.5–4 Hz) power was not different in CB1 KO mice, but during recovery from forced sleep deprivation, KO mice had reduced NREM delta power and increased sleep fragmentation. Overall, these findings demonstrate that the EC system actively regulates cortical up-states and important features of NREM sleep such as its duration and low frequency cortical oscillations.
Highlights
Low frequency oscillations in electrical activity called slowwaves (0.5–4 Hz) become the dominant pattern of cortical activity when sensory input to cortical networks is reduced, for instance during deep-stage non-REM (NREM) sleep, anesthesia, and in cerveau isole preparations [1]
AEA synthesis occurs via several different pathways [19] while the enzyme fatty acid amide hydrolase (FAAH; [20]) is primarily responsible for its inactivation. 2-AG is synthesized via a rate-limiting step catalyzed by diacylglycerol lipase (DAGL), and is inactivated through monoacylglycerol lipase (MAGL)-mediated hydrolysis
We found that the EC system modulates up-states in medial prefrontal cortex (PFC) pyramidal neurons (PNs), sleep-wake states, and delta frequency oscillations during NREM
Summary
Low frequency oscillations in electrical activity called slowwaves (0.5–4 Hz) become the dominant pattern of cortical activity when sensory input to cortical networks is reduced, for instance during deep-stage non-REM (NREM) sleep, anesthesia, and in cerveau isole preparations [1]. Up-states are modulated by monoaminergic inputs arising from midbrain and brainstem structures [4,5,6,7]. Organotypic cortical cultures lacking monoaminergic inputs still actively generate upstates [7,8,9] suggesting that extra-cortical neuromodulators are not essential for this form of network activity. It is not known whether activity within and between pyramidal neurons (PNs) and interneurons in the cortical microcircuitry may act synergistically with intrinsic neuromodulatory systems to regulate network activity
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