Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.

Long-term potentiation (LTP) of excitatory synaptic transmission has long been considered a cellular correlate for learning and memory1,2. Early LTP (eLTP, <1 hour) had initially been explained either by presynaptic increases in glutamate release3–5 or by direct modification of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function6,7. Compelling models have more recently proposed that synaptic potentiation can occur by the recruitment of additional post-synaptic AMPARs8, sourced either from an intracellular reserve pool by exocytosis or from nearby extra synaptic receptors pre-existing on the neuronal surface9–12. However, the exact mechanism through which synapses can rapidly recruit new AMPARs during eLTP is still unknown. In particular, direct evidence for a pivotal role of AMPAR surface diffusion as a trafficking mechanism in synaptic plasticity is still lacking. Using AMPAR immobilization approaches, we show that interfering with AMPAR surface diffusion dramatically impaired synaptic potentiation of Schaffer collateral/commissural inputs to cornu ammonis area 1 (CA1) in cultured slices, acute slices and in vivo. Our data also identifies distinct contributions of various AMPAR trafficking routes to the temporal profile of synaptic potentiation. In addition, AMPAR immobilization in vivo in the dorsal hippocampus (DH) before fear conditioning, indicated that AMPAR diffusion is important for the early phase of contextual learning. Therefore, our results provide a direct demonstration that the recruitment of new receptors to synapses by surface diffusion is a critical mechanism for the expression of LTP and hippocampal learning. Since AMPAR surface diffusion is dictated by weak Brownian forces that are readily perturbed by protein-protein interactions, we anticipate that this fundamental trafficking mechanism will be a key target for modulating synaptic potentiation and learning.

Autoimmune synaptic encephalitides are recently described human brain diseases leading to psychiatric and neurological syndromes through inappropriate brain-autoantibody interactions. The most frequent synaptic autoimmune encephalitis is associated with autoantibodies against extracellular domains of the glutamatergic N-methyl-d-aspartate receptor, with patients developing psychotic and neurological symptoms in an autoantibody titre-dependent manner. Although N-methyl-d-aspartate receptors are the primary target of these antibodies, the cellular and molecular pathway(s) that rapidly lead to N-methyl-d-aspartate receptor dysfunction remain poorly understood. In this report, we used a unique combination of high-resolution nanoparticle and bulk live imaging approaches to demonstrate that anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis strongly alter, in a time-dependent manner, the surface content and trafficking of GluN2-NMDA receptor subtypes. Autoantibodies laterally displaced surface GluN2A-NMDA receptors out of synapses and completely blocked synaptic plasticity. This loss of extrasynaptic and synaptic N-methyl-d-aspartate receptor is prevented both in vitro and in vivo, by the activation of EPHB2 receptors. Indeed, the anti-N-methyl-d-aspartate receptor autoantibodies weaken the interaction between the extracellular domains of the N-methyl-d-aspartate and Ephrin-B2 receptors. Together, we demonstrate that the anti-N-methyl-d-aspartate receptor autoantibodies from patients with encephalitis alter the dynamic retention of synaptic N-methyl-d-aspartate receptor through extracellular domain-dependent mechanism(s), shedding new light on the pathology of the neurological and psychiatric disorders observed in these patients and opening possible new therapeutic strategies.

We examined the role of excitatory amino acids (EAAs) in the activation of midbrain dopaminergic (DA) neurons evoked by stimulation of the ventromedial and ventrolateral (subcommissural) bed nucleus of the stria terminalis (vBNST). Using anesthetized rats and extracellular recording techniques, we found that 84.8% of ventral tegmental area (VTA) DA neurons were activated synaptically by single-pulse electrical stimulation of the vBNST. In contrast, similar stimulation did not affect the activity of presumed GABA neurons in the VTA. Three characteristic responses were observed in VTA DA neurons: short latency activation (<25 msec; 55.1% of cells), long latency activation (>65 msec; 56% of cells), and inhibition (61.8% of cells, usually followed by long latency excitation). Microinfusion of antagonists of EAA receptors (3 mm kynurenic acid, 100 microm AP-5, or 50 microm CNQX) from a micropipette adjacent to the recording electrode significantly reduced both short and long latency activations evoked in DA neurons by vBNST stimulation. Specific responses were attenuated similarly by AP-5 alone, CNQX alone, or a cocktail of AP-5+CNQX, indicating that joint activation of NMDA plus non-NMDA receptors was required. Stimulation of the vBNST by local microinfusion of glutamate increased the firing and bursting activity of VTA DA neurons. Similar microinfusion of GABA decreased bursting of VTA DA neurons without altering their firing rate. Retrograde and anterograde labeling and antidromic activation of vBNST neurons by VTA stimulation confirmed a direct projection from the vBNST to the VTA. These results reveal that inputs from the vBNST exert a strong excitatory influence on VTA DA neurons mediated by both NMDA and non-NMDA receptors.

Morphine is a highly potent analgesic with high addictive potential in specific contexts. Although dopamine neurons of the ventral tegmental area (VTA) are widely believed to play an essential role in the development of drug addiction, neuronal circuits underlying morphine action on dopamine neurons have not been fully elucidated. Here we combined in vivo electrophysiology, tract-tracing experiments, and targeted neuronal inactivation to dissect a neural circuit for acute morphine action on dopamine neurons in rats. We found that in vivo, morphine targets the GABAergic tail of the VTA, also called the rostromedial tegmental nucleus, to increase the firing of dopamine neurons through the activation of VTA μ opioid receptors expressed on tail of the VTA/rostromedial tegmental nucleus efferents. Our data also reveal that in the absence of VTA glutamatergic tone, there is no morphine-induced activation of dopamine neurons. These results define the anatomical organization and functional role of a neural circuit for acute morphine action on dopamine neurons.

Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB receptors from astroglial cells (GFAP-CB-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB receptors increased intracellular astroglial Ca levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB-KO displayed lower occupancy of the co-agonist binding site of synaptic hippocampal NMDARs. Finally, elevation of D-serine levels fully rescued LTP and memory impairments of GFAP-CB-KO mice. These data reveal a novel mechanism of in vivo astroglial control of memory and synaptic plasticity via the D-serine-dependent control of NMDARs.

A new mesopontine structure exerting a strong influence on dopamine systems has been recently defined: the tail of the ventral tegmental area / rostromedial tegmental nucleus (tVTA/RMTg). This review presents a neuroanatomical, physiological and behavioral overview of some of the recent and ongoing research on this brain region and its relationship with dopamine systems. The tVTA/RMTg sends dense GABA projections to VTA and substantia nigra neurons. The inhibitory influence of tVTA/RMTg on dopamine neurons is supported by both neuroanatomical and electrophysiology data. The latter studies also reveal the tVTA/RMTg as a substrate for morphine and cannabinoid action on dopamine cells. In primates, the tVTA/RMTg has been implicated in reward prediction error signals, through a basal ganglia - lateral habenula -tVTA/RMTg - dopamine - basal ganglia circuit. In rodents, the tVTA/RMTg has been shown to play a critical role in aversive behaviors, particularly those involving behavioral inhibition, such as freezing and avoidance. These findings highlight the functional importance of the tVTA/RMTg as a major GABA brake for dopamine systems.

The reason why neurons synthesize more than one endocannabinoid (eCB) and how this is involved in the regulation of synaptic plasticity in a single neuron is not known. We found that 2-arachidonoylglycerol (2-AG) and anandamide mediate different forms of plasticity in the extended amygdala of rats. Dendritic L-type Ca(2+) channels and the subsequent release of 2-AG acting on presynaptic CB1 receptors triggered retrograde short-term depression. Long-term depression was mediated by postsynaptic mGluR5-dependent release of anandamide acting on postsynaptic TRPV1 receptors. In contrast, 2-AG/CB1R-mediated retrograde signaling mediated both forms of plasticity in the striatum. These data illustrate how the eCB system can function as a polymodal signal integrator to allow the diversification of synaptic plasticity in a single neuron.