Wiring and firing neuronal networks: endocannabinoids take center stage

Endocannabinoids (eCBs) function as retrograde messengers at both excitatory and inhibitory synapses, and control various forms of synaptic plasticity in the adult brain. The molecular machinery required for specific eCB functions during synaptic plasticity is well established. However, eCB signaling plays surprisingly fundamental roles in controlling the acquisition of neuronal identity during CNS development. Recent work suggests that selective recruitment of regulatory signaling networks to CB₁ cannabinoid receptors dictates neuronal state-change decisions. In addition, the spatial localization and temporal precision of eCB actions emerges as a novel organizer in developing neuronal networks. Current challenges include fitting novel molecular candidates into regulatory eCB signaling pathways, and defining the temporal dynamics of context-dependent signaling mechanisms underpinning particular neuronal specification events.

Introduction

Synaptic communication in complex neuronal networks relies on the coincident activity of integrated feedback mechanisms allowing optimal temporal refinement of activity-dependent synaptic connectivity [1]. Generation and maintenance of the structural and functional coherence of neuronal circuits is the basic cellular principle of higher brain functions. Thus, multiple mechanisms have evolved during brain development to allow the temporal refinement of neuronal excitability. Although redundancy at the level of coexistent signaling networks with partially overlapping functions ensures the continuous adaptation of presynaptic and postsynaptic components between connected neurons, retrograde synaptic signaling emerges as a uniquely powerful means to tune the temporal and spatial efficacy of synaptic information transfer.

During the past decade, several retrograde messengers have been identified (Figure 1) that exhibit robust differences in their speed of affecting synaptic integration, temporal flexibility and efficiency, and spatial precision [2, 3•, 4•, 5, 6, 7]. Endocannabinoid (eCB) signaling represents a key retrograde signaling pathway [8] for tuning both homosynaptic and heterosynaptic plasticity [9] in the postnatal brain. The general molecular paradigm is that eCBs are synthesized postsynaptically in an activity-dependent manner and engage presynaptic CB₁ cannabinoid receptors (CB₁Rs) on both excitatory and inhibitory afferents thus decreasing neurotransmitter release. Four basic forms of eCB-mediated synaptic plasticity have been described (Figure 1) [8, 9, 10]: Firstly, in depolarization-induced suppression of inhibition (DSI), the depolarization of a postsynaptic neuron stimulates eCB production that activates presynaptic CB₁Rs at GABAergic interneuron terminals, leading to a decrease in inhibitory neurotransmission. eCBs produced in the same fashion acting on CB₁R on excitatory neurons evoke depolarization-induced suppression of excitation (DSE). Secondly, in metabotropic suppression of inhibition (MSI), the activation of postsynaptic G_q/11-linked receptors (typically M₁ or M₃ muscarinic acetylcholine receptors or group I metabotropic glutamate receptors [mGluRs]) leads to production of eCBs activating presynaptic CB₁Rs thus decreasing inhibitory neurotransmission. As before, when eCBs produced in this fashion activate CB₁Rs on excitatory terminals, the process is termed metabotropic suppression of excitation (MSE). Thirdly, eCB-mediated long-term depression (LTD) is evoked during the sustained stimulation of group I mGluRs, as might happen during the prolonged low-frequency stimulation of excitatory pathways. LTD can affect either the stimulated pathway (homosynaptic LTD) or a neighboring pathway (heterosynaptic LTD), if the terminals of the neighboring pathway express CB₁Rs. Fourthly, in slow-self inhibition (SSI), eCBs are produced following the repetitive depolarization of a neuron and activate CB₁Rs on the same neuron, opening inwardly rectifying potassium channels and causing sustained hyperpolarization of the neuron [11]. SSI is remarkable since in this form of eCB-mediated plasticity eCBs are produced and act in the same cell, as opposed to being retrograde messengers in the other forms. It should be noted that since eCBs can inhibit both excitatory and inhibitory neurotransmission, their net effect at the circuit level, also influenced by the coincident presence of other factors, can be either inhibitory or stimulatory.

Molecular determinants of eCB-mediated retrograde signaling at central synapses appear to be developmentally organized such that they can feedback to control the earliest events of presynaptic neurotransmitter release during the transition from synaptogenesis to synaptic communication in developing neuronal circuits [12••, 13]. This leads to the question whether molecular underpinnings of eCB signaling loops acting so efficiently in the postnatal brain subserve particular physiological functions during brain development. The answer appears to be yes, but we are far from understanding the molecular logic and temporal dynamics of eCB signaling networks in the embryonic brain, and how their specific neurodevelopmental functions relate to and define their retrograde control of neurotransmitter release at mature synapses. Important open questions include: where and when eCBs are produced in the developing brain; the molecular identity of eCBs and whether they represent ‘active’ signals; whether respective receptors and intracellular signal transduction cascades differ from those in the postnatal brain; how eCB signaling integrates with other regulatory systems; and how the relative power of this newly emerging signaling entity contributes to the defining of neurodevelopmental processes. In this review, we focus on the recent discoveries establishing eCB-driven cellular identification events in the developing cerebrum, and define a unifying concept of how eCB signaling provides positional signals for excitatory and inhibitory afferents along the dendritic tree of cortical neurons, thus shaping the complexity of cortical connectivity.