Manuel Mameli

Synaptic plasticity and addiction: Learning mechanisms gone awry

Experience-dependent changes in synaptic strength, or synaptic plasticity, may underlie many learning processes. In the reward circuit for example, synaptic plasticity may serve as a cellular substrate for goal-directed behaviors. Addictive drugs, through a surge of dopamine released from neurons of the ventral tegmental area, induce widespread synaptic adaptations within this neuronal circuit. Such drug-evoked synaptic plasticity may constitute an early cellular mechanism eventually causing compulsive drug-seeking behavior in some drug users. In the present review we will discuss how different classes of addictive drugs cause an increase of dopamine release and describe their effects on synapses within the mesolimbic dopamine system. We will emphasize the early synaptic changes in the ventral tegmental area common to all additive drugs and go on to show how these adaptations may reorganize neuronal circuits, eventually leading to behaviors that define addiction.

Expression of Cocaine-Evoked Synaptic Plasticity by GluN3A-Containing NMDA Receptors

Drug-evoked synaptic plasticity in the mesolimbic dopamine (DA) system reorganizes neural circuits that may lead to addictive behavior. The first cocaine exposure potentiates AMPAR excitatory postsynaptic currents (EPSCs) onto DA neurons of the VTA but reduces the amplitude of NMDAR-EPSCs. While plasticity of AMPAR transmission is expressed by insertion of calcium (Ca(2+))-permeable GluA2-lacking receptors, little is known about the expression mechanism for altered NMDAR transmission. Combining ex vivo patch-clamp recordings, mouse genetics, and subcellular Ca(2+) imaging, we observe that cocaine drives the insertion of NMDARs that are quasi-Ca(2+)-impermeable and contain GluN3A and GluN2B subunits. These GluN3A-containing NMDARs appear necessary for the expression of cocaine-evoked plasticity of AMPARs. We identify an mGluR1-dependent mechanism to remove these noncanonical NMDARs that requires Homer/Shank interaction and protein synthesis. Our data provide insight into the early cocaine-driven reorganization of glutamatergic transmission onto DA neurons and offer GluN3A-containing NMDARs as new targets in drug addiction.

Synaptic and cellular profile of neurons in the lateral habenula

The lateral habenula (LHb) is emerging as a crucial structure capable of conveying rewarding and aversive information. Recent evidence indicates that a rapid increase in the activity of LHb neurons drives negative states and avoidance. Furthermore, the hyperexcitability of neurons in the LHb, especially those projecting to the midbrain, may represent an important cellular correlate for neuropsychiatric disorders like depression and drug addiction. Despite the recent insights regarding the implications of the LHb in the context of reward and aversion, the exact nature of the synaptic and cellular players regulating LHb neuronal functions remains largely unknown. Here we focus on the synaptic and cellular physiology of LHb neurons. First, we discuss the properties of excitatory transmission and the implications of glutamate receptors for long-term synaptic plasticity; second, we review the features of GABAergic transmission onto LHb neurons; and finally, we describe the contribution that neuromodulators such as dopamine (DA) and serotonin may have for LHb neuronal physiology. We relate these findings to the role that the LHb can play in processing aversive and rewarding stimuli, both in health and disease states.

GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper.

Endoplasmic reticulum (ER) release and cell-surface export of many G protein-coupled receptors (GPCRs) are tightly regulated. For gamma-aminobutyric acid (GABA)B receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell-surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gatekeepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function.

The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3−/− mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3−/− mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

Ventral Subiculum Stimulation Promotes Persistent Hyperactivity of Dopamine Neurons and Facilitates Behavioral Effects of Cocaine

The ventral subiculum (vSUB) plays a key role in addiction, and identifying the neuronal circuits and synaptic mechanisms by which vSUB alters the excitability of dopamine neurons is a necessary step to understand the motor changes induced by cocaine. Here, we report that high-frequency stimulation of the vSUB (HFSvSUB) over-activates ventral tegmental area (VTA) dopamine neurons in vivo and triggers long-lasting modifications of synaptic transmission measured ex vivo. This potentiation is caused by NMDA-dependent plastic changes occurring in the bed nucleus of the stria terminalis (BNST). Finally, we report that the modification of the BNST-VTA neural circuits induced by HFSvSUB potentiates locomotor activity induced by a sub-threshold dose of cocaine. Our findings unravel a neuronal circuit encoding behavioral effects of cocaine in rats and highlight the importance of adaptive modifications in the BNST, a structure that influences motivated behavior as well as maladaptive behaviors associated with addiction.

mGluR-Dependent Synaptic Plasticity in Drug-Seeking

A primary feature of drug addiction is the compulsive use despite negative consequences. A general consensus is emerging on the capacity of addictive substances to co-opt synaptic transmission and synaptic plasticity in brain circuits which are involved in reinforcement and reward processing. A current hypothesis is that drug-driven neuroadaptations during learning and memory processes divert the functions of these brain circuits, eventually leading to addictive behaviors. Metabotropic glutamate receptors (mGluRs) not only lead to long-term modulation of synaptic transmission but they have been implicated in drug-evoked synaptic plasticity and drug-seeking behaviors in two important ways. mGluR-dependent modulation of synaptic transmission is impaired by drug experience but interestingly their activation has been indicated as a strategy to restore baseline transmission after drug-evoked synaptic plasticity. Here we focus on the cellular mechanisms underlying mGluR-dependent long-term changes of excitatory synapses, and review results implicating these receptors in drug-evoked synaptic plasticity.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons’ activity and stress-related behaviors, such as social aversion. Blocking β2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.

Your ticket to independence: a guide to getting your first Principal Investigator position

The transition to scientific independence as a principal investigator (PI) can seem like a daunting and mysterious process to postdocs and students ‐ something that many aspire to while at the same time wondering how to achieve this goal and what being a PI really entails. The FENS Kavli Network of Excellence (FKNE) is a group of young faculty who have recently completed this step in various fields of neuroscience across Europe. In a series of opinion pieces from FKNE scholars, we aim to demystify this process and to offer the next generation of up‐and‐coming PIs some advice and personal perspectives on the transition to independence, starting here with guidance on how to get hired to your first PI position. Rather than providing an exhaustive overview of all facets of the hiring process, we focus on a few key aspects that we have learned to appreciate in the quest for our own labs: What makes a research programme exciting and successful? How can you identify great places to apply to and make sure your application stands out? What are the key objectives for the job talk and the interview? How do you negotiate your position? And finally, how do you decide on a host institute that lets you develop both scientifically and personally in your new role as head of a lab?

Positive regulation of raphe serotonin neurons by serotonin 2B receptors

Serotonin is a neurotransmitter involved in many psychiatric diseases. In humans, a lack of 5-HT2B receptors is associated with serotonin-dependent phenotypes, including impulsivity and suicidality. A lack of 5-HT2B receptors in mice eliminates the effects of molecules that directly target serotonergic neurons including amphetamine derivative serotonin releasers, and selective serotonin reuptake inhibitor antidepressants. In this work, we tested the hypothesis that 5-HT2B receptors directly and positively regulate raphe serotonin neuron activity. By ex vivo electrophysiological recordings, we report that stimulation by the 5-HT2B receptor agonist, BW723C86, increased the firing frequency of serotonin Pet1-positive neurons. Viral overexpression of 5-HT2B receptors in these neurons increased their excitability. Furthermore, in vivo 5-HT2B-receptor stimulation by BW723C86 counteracted 5-HT1A autoreceptor-dependent reduction in firing rate and hypothermic response in wild-type mice. By a conditional genetic ablation that eliminates 5-HT2B receptor expression specifically and exclusively from Pet1-positive serotonin neurons (Htr2b5-HTKO mice), we demonstrated that behavioral and sensitizing effects of MDMA (3,4-methylenedioxy-methamphetamine), as well as acute behavioral and chronic neurogenic effects of the antidepressant fluoxetine, require 5-HT2B receptor expression in serotonergic neurons. In Htr2b5-HTKO mice, dorsal raphe serotonin neurons displayed a lower firing frequency compared to control Htr2blox/lox mice as assessed by in vivo extracellular recordings and a stronger hypothermic effect of 5-HT1A-autoreceptor stimulation was observed. The increase in head-twitch response to DOI (2,5-dimethoxy-4-iodoamphetamine) further confirmed the lower serotonergic tone resulting from the absence of 5-HT2B receptors in serotonin neurons. Together, these observations indicate that the 5-HT2B receptor acts as a direct positive modulator of serotonin Pet1-positive neurons in an opposite way as the known 5-HT1A-negative autoreceptor.