Christian Lüscher

Role of AMPA Receptor Cycling in Synaptic Transmission and Plasticity

Compounds known to disrupt exocytosis or endocytosis were introduced into CA1 pyramidal cells while monitoring excitatory postsynaptic currents (EPSCs). Disrupting exocytosis or the interaction of GluR2 with NSF caused a gradual reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC but prevented the subsequent induction of LTD. These results suggest that AMPARs, but not NMDARs, cycle into and out of the synaptic membrane at a rapid rate and that certain forms of synaptic plasticity may utilize this dynamic process.

G Protein-Coupled Inwardly Rectifying K+ Channels (GIRKs) Mediate Postsynaptic but Not Presynaptic Transmitter Actions in Hippocampal Neurons

To study the role of G protein-coupled, inwardly rectifying K+ (GIRK) channels in mediating neurotransmitter actions in hippocampal neurons, we have examined slices from transgenic mice lacking the GIRK2 gene. The outward currents evoked by agonists for GABA(B) receptors, 5HT1A receptors, and adenosine A1 receptors were essentially absent in mutant mice, while the inward current evoked by muscarinic receptor activation was unaltered. In contrast, the presynaptic inhibitory action of a number of presynaptic receptors on excitatory and inhibitory terminals was unaltered in mutant mice. These included GABA(B), adenosine, muscarinic, metabotropic glutamate, and NPY receptors on excitatory synapses and GABA(B) and opioid receptors on inhibitory synapses. These findings suggest that a number of G protein-coupled receptors activate the same class of postsynaptic K+ channel, which contains GIRK2. In addition, the GIRK2 channels play no role in the inhibition mediated by presynaptic G protein-coupled receptors, suggesting that the same receptor can couple to different effector systems according to its subcellular location in the neuron.

Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling

Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior.

Epilepsy, Hyperalgesia, Impaired Memory, and Loss of Pre- and Postsynaptic GABA B Responses in Mice Lacking GABA B(1)

GABA(B) (gamma-aminobutyric acid type B) receptors are important for keeping neuronal excitability under control. Cloned GABA(B) receptors do not show the expected pharmacological diversity of native receptors and it is unknown whether they contribute to pre- as well as postsynaptic functions. Here, we demonstrate that Balb/c mice lacking the GABA(B(1)) subunit are viable, exhibit spontaneous seizures, hyperalgesia, hyperlocomotor activity, and memory impairment. Upon GABA(B) agonist application, null mutant mice show neither the typical muscle relaxation, hypothermia, or delta EEG waves. These behavioral findings are paralleled by a loss of all biochemical and electrophysiological GABA(B) responses in null mutant mice. This demonstrates that GABA(B(1)) is an essential component of pre- and postsynaptic GABA(B) receptors and casts doubt on the existence of proposed receptor subtypes.

Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease.

Many excitatory synapses express Group 1, or Gq coupled, metabotropic glutamate receptors (Gp1 mGluRs) at the periphery of their postsynaptic density. Activation of Gp1 mGluRs typically occurs in response to strong activity and triggers long-term plasticity of synaptic transmission in many brain regions, including the neocortex, hippocampus, midbrain, striatum, and cerebellum. Here we focus on mGluR-induced long-term synaptic depression (LTD) and review the literature that implicates Gp1 mGluRs in the plasticity of behavior, learning, and memory. Moreover, recent studies investigating the molecular mechanisms of mGluR-LTD have discovered links to mental retardation, autism, Alzheimers disease, Parkinsons disease, and drug addiction. We discuss how mGluRs lead to plasticity of neural circuits and how the understanding of the molecular mechanisms of mGluR plasticity provides insight into brain disease.

Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease

G protein-gated inwardly rectifying potassium (GIRK) channels hyperpolarize neurons in response to activation of many different G protein-coupled receptors and thus control the excitability of neurons through GIRK-mediated self-inhibition, slow synaptic potentials and volume transmission. GIRK channel function and trafficking are highly dependent on the channel subunit composition. Pharmacological investigations of GIRK channels and studies in animal models suggest that GIRK activity has an important role in physiological responses, including pain perception and memory modulation. Moreover, abnormal GIRK function has been implicated in altering neuronal excitability and cell death, which may be important in the pathophysiology of diseases such as epilepsy, Downs syndrome, Parkinsons disease and drug addiction. GIRK channels may therefore prove to be a valuable new therapeutic target.

Bi-directional effects of GABA B receptor agonists on the mesolimbic dopamine system

The rewarding effect of drugs of abuse is mediated by activation of the mesolimbic dopamine system, which is inhibited by putative anti-craving compounds. Interestingly, different GABAB receptor agonists can exert similarly opposing effects on the reward pathway, but the cellular mechanisms involved are unknown. Here we found that the coupling efficacy (EC50) of G-protein-gated inwardly rectifying potassium (GIRK, Kir3) channels to GABAB receptor was much lower in dopamine neurons than in GABA neurons of the ventral tegmental area (VTA), depending on the differential expression of GIRK subunits. Consequently, in rodent VTA slices, a low concentration of the canonical agonist baclofen caused increased activity, whereas higher doses eventually inhibited dopamine neurons. At behaviorally relevant dosages, baclofen activated GIRK channels in both cell types, but the drug of abuse γ-hydroxy-butyric acid (GHB) activated GIRK channels only in GABAergic neurons. Thus GABAB receptor agonists exert parallel cellular and behavioral effects due to the cell-specific expression of GIRK subunits.

GABA Neurons of the VTA Drive Conditioned Place Aversion

Salient but aversive stimuli inhibit the majority of dopamine (DA) neurons in the ventral tegmental area (VTA) and cause conditioned place aversion (CPA). The cellular mechanism underlying DA neuron inhibition has not been investigated and the causal link to behavior remains elusive. Here, we show that GABA neurons of the VTA inhibit DA neurons through neurotransmission at GABA(A) receptors. We also observe that GABA neurons increase their firing in response to a footshock and provide evidence that driving GABA neurons with optogenetic effectors is sufficient to affect behavior. Taken together, our data demonstrate that synaptic inhibition of DA neurons drives place aversion.

NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD)

Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor-dependent LTP and LTD may constitute cellular substrates of learning and memory.

Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc

Addictive drugs hijack mechanisms of learning and memory that normally underlie reinforcement of natural rewards and induce synaptic plasticity of glutamatergic transmission in the mesolimbic dopamine (DA) system. In the ventral tegmental area (VTA), a single exposure to cocaine efficiently triggers NMDA receptor–dependent synaptic plasticity in DA neurons, whereas plasticity in the nucleus accumbens (NAc) occurs only after repeated injections. Whether these two forms of plasticity are independent or hierarchically organized remains unknown. We combined ex vivo electrophysiology in acute brain slices with behavioral assays modeling drug relapse in mice and found that the duration of the cocaine-evoked synaptic plasticity in the VTA is gated by mGluR1. Overriding mGluR1 in vivo made the potentiation in the VTA persistent. This led to synaptic plasticity in the NAc, which contributes to cocaine-seeking behavior after protracted withdrawal. Impaired mGluR1 function in vulnerable individuals could represent a first step in the recruitment of the neuronal network that underlies drug addiction.