Wiring and firing neuronal networks: endocannabinoids take center stage
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 Gq/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.
Section snippets
Molecular logic of endocannabinoid signaling sculpted by developmental principles
2-Arachidonoylglycerol (2-AG) and anandamide (AEA), members of the eCB family of neuroactive lipids, are primarily synthesized by sn-1-diacylglycerol lipase α/β (DAGLα/β) [14••] and α/β-hydrolase 4/glycerophosphodiesterase 1 (ABDH4/GDE-1) [15] and bind to cannabinoid receptors in the brain (Figure 1) and at the periphery. 2-AG and AEA promiscuously activate CB1, CB2 (CB1/2R), and other cannabinoid receptors including GPR55 [16]. However, the identity of eCBs and bioactive lipids stimulating
Expression dictates function: context-dependent signaling at CB1 cannabinoid receptors
The existence of eCB ligands and CB1Rs in the developing rodent and human brain triggered an initial wave of interest when CB1Rs were unequivocally identified as the targets of Δ9-tetrahydrocannabinol (THC) from cannabis [30]. It took almost another decade for the cellular specificity, functions, and interacting partners of eCB signaling networks affecting CNS patterning to emerge. In fact, both 2-AG and AEA are present in the developing CNS from the very early stages of differentiation, though
Endocannabinoids define synapse positioning
The establishment of long-range excitatory axons by pyramidal cells precedes the neurochemical specification and synapse patterning of GABAergic interneurons during corticogenesis. Prominent DAGLα/β localization to pyramidal cell axons is required for axonal elongation through cell-autonomous signaling [33••, 37] (Figure 3). De novo synthesized 2-AG can exert either autocrine regulation via CB1Rs distributed along the longitudinal axis of the growing axon, or paracrine signaling among
Therapeutic implications
The neurodevelopmental impact of THC exposure during pregnancy has recently gained considerable attention given the long-lasting effects of prenatal cannabis use on emotional control, social behaviors, and cognition in affected offspring [46]. THC may be deleterious, acting as an agonist or an antagonist. Since THC is an intermediate potency, low efficacy CB1R agonist, THC can potentially antagonize the actions of the more efficacious 2-AG in vivo. Thus, in addition to activating CB1Rs, THC
Conclusions
The eCB system is emerging as a key regulatory signaling network fundamental to the wiring of the brain during development with an array of functions ranging from lineage segregation of stem cells to refinement of synaptic functions in complex neuronal networks. We have recently experienced a quantum leap in understanding the molecular hierarchy and signaling principles selectively governed by eCB signals in the embryonic brain. Nevertheless, the key unresolved question remains to define the
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the Swedish Medical Research Council (TH), Scottish Universities Life Science Alliance (TH), Alzheimer’s Association (KM, TH), European Molecular Biology Organization Young Investigator Programme (TH), European Commission (HEALTH-F2-2007-201159; TH), National Institutes of Health Grants DA023214 (TH), DA11322 (KM), DA15916 (KM), DA21969 (KM), and BBSRC (PD).
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