Lawrence Fourgeaud

A Single In Vivo Exposure to Cocaine Abolishes Endocannabinoid-Mediated Long-Term Depression in the Nucleus Accumbens

In the nucleus accumbens (NAc), a key structure to the effects of all addictive drugs, presynaptic cannabinoid CB1 receptors (CB1Rs) and postsynaptic metabotropic glutamate 5 receptors (mGluR5s) are the principal effectors of endocannabinoid (eCB)-mediated retrograde long-term depression (LTD) (eCB-LTD) at the prefrontal cortex-NAc synapses. Both CB1R and mGluR5 are involved in cocaine-related behaviors; however, the impact of in vivo cocaine exposure on eCB-mediated retrograde synaptic plasticity remains unknown. Electrophysiological and biochemical approaches were used, and we report that a single in vivo cocaine administration abolishes eCB-LTD. This effect of cocaine was not present in D1 dopamine receptor (D1R) -/- mice and was prevented when cocaine was coadministered with the selective D1R antagonist 8-chloro-2,3,4,5-tetrahydro-3-5-1h-3-benzazepin-7-ol (0.5 mg/kg) or with the NMDA receptor (NMDAR) blocker (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate (1 mg/kg), suggesting the involvement of D1R and NMDAR. We found that the cocaine-induced blockade of retrograde signaling was correlated with enhanced expression levels of Homer scaffolding proteins containing the coiled-coil domain and accompanied by a strong reduction of mGluR5 surface expression. The results suggest that cocaine-induced loss of eCB retrograde signaling is caused by a reduction in the ability of mGluR5 to translate anterograde glutamate transmission into retrograde eCB signaling.

TAM receptors regulate multiple features of microglial physiology

Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson’s disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.

MHC class I modulates NMDA receptor function and AMPA receptor trafficking.

Proteins of the major histocompatibility complex class I (MHCI) are known for their role in immunity and have recently been implicated in long-term plasticity of excitatory synaptic transmission. However, the mechanisms by which MHCI influences synaptic plasticity remain unknown. Here we show that endogenous MHCI regulates synaptic responses mediated by NMDA-type glutamate receptors (NMDARs) in the mammalian central nervous system (CNS). The AMPA/NMDA ratio is decreased at MHCI-deficient hippocampal synapses, reflecting an increase in NMDAR-mediated currents. This enhanced NMDAR response is not associated with changes in the levels, subunit composition, or gross subcellular distribution of NMDARs. Increased NMDAR-mediated currents in MHCI-deficient neurons are associated with characteristic changes in AMPA receptor trafficking in response to NMDAR activation. Thus, endogenous MHCI tonically inhibits NMDAR function and controls downstream NMDAR-induced AMPA receptor trafficking during the expression of plasticity.

Synapse Remodeling, Compliments of the Complement System

A growing body of evidence indicates that some proteins known for their immune functions also have distinct nonimmune functions in the normal uninjured central nervous system. In this issue, Stevens et al. (2007) demonstrate an unexpected requirement for molecules of the complement cascade in the remodeling of synaptic connections in the developing visual system.

Active surface transport of metabotropic glutamate receptors through binding to microtubules and actin flow

Receptors for neurotransmitters are concentrated and stabilized at given sites such as synapses through interactions with scaffolding proteins and cytoskeletal elements. The transport of receptors first involves directed vesicular trafficking of intracellularly stored receptors followed by their targeting to the plasma membrane. Once expressed at the cell surface, receptors are thought to reach their final location by random Brownian diffusion in the plasma membrane plane. Here, we investigate whether the metabotropic glutamate receptor mGluR5 can also be transported actively on the cell surface. We used single particle tracking to follow mGluR5 movement in real time at the surface of neuronal growth cones or fibroblast lamellipodia, both of which bear a particularly active cytoskeleton. We found that after a certain lag time mGluR5 undergoes directed rearward transport, which depends on actin flow. On actin depolymerization, directed movement was suppressed, but receptors still bound to a rigid structure. By contrast, receptor transport and immobilization was fully suppressed by microtubule depolymerization but favored by microtubule stabilization. Furthermore, mGluR5 could be immunoprecipitated with tubulin from rat brains, confirming the ability of mGluR5 to bind to microtubules. We propose that mGluR5 can be transported on the cell surface through actin-mediated retrograde transport of microtubules. This process may play a role in receptor targeting and organization during synapse formation or during glutamate-mediated growth cone chemotaxis.

Role of immune molecules in the establishment and plasticity of glutamatergic synapses

An increasing number of studies support an unexpected role for immune molecules in regulating healthy brain functions during development and in adulthood. Here we review the roles of specific immune molecules (including cytokines, components of the complement cascade, and members of the major histocompatibility complex class I family and their receptors) in the formation and plasticity of glutamatergic synapses. These findings add a new dimension to our understanding of neural–immune interactions, and suggest novel molecular mechanisms that may underlie the modification of glutamatergic synapses in both normal and pathological states.

Differential Effects of UCHL1 Modulation on Alpha-Synuclein in PD-Like Models of Alpha-Synucleinopathy

Parkinsons disease (PD) is a progressive neurodegenerative disorder caused by genetic and environmental factors. Abnormal accumulation and aggregation of alpha-synuclein (a-syn) within neurons, and mutations in the a-syn and UCH-L1 genes have been shown to play a role in the pathogenesis of PD. In light of recent reports suggesting an interaction between a-synuclein and UCH-L1, we investigated the effects of UCH-L1 inhibition on a-syn distribution and expression levels in primary neurons and hippocampal tissues derived from non transgenic (non tg) and a-syn over expressing tg mice. We show that suppression of UCH-L1 activity increased a-syn levels in control, non tg neurons, and resulted in a concomitant accumulation of presynaptic a-syn in these neurons. In contrast, blocking UCH-L1 activity in a-syn over expressing neurons decreased a-syn levels, and enhanced its synaptic clearance. In vitro studies verified the LDN-induced inhibition of UCH-L1 had minimal effect on LC3 (a marker of autophagy) in control cells, in cells over expressing a-syn UCH-L1 inhibition resulted in increased LC3 activity. These findings suggest a possible differential role of UCH-L1 function under normal and pathological conditions. Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain.

MHC Class I Limits Hippocampal Synapse Density by Inhibiting Neuronal Insulin Receptor Signaling

Proteins of the major histocompatibility complex class I (MHCI) negatively regulate synapse density in the developing vertebrate brain (Glynn et al., 2011; Elmer et al., 2013; Lee et al., 2014), but the underlying mechanisms remain largely unknown. Here we identify a novel MHCI signaling pathway that involves the inhibition of a known synapse-promoting factor, the insulin receptor. Dominant-negative insulin receptor constructs decrease synapse density in the developing Xenopus visual system (Chiu et al., 2008), and insulin receptor activation increases dendritic spine density in mouse hippocampal neurons in vitro (Lee et al., 2011). We find that genetically reducing cell surface MHCI levels increases synapse density selectively in regions of the hippocampus where insulin receptors are expressed, and occludes the neuronal insulin response by de-repressing insulin receptor signaling. Pharmacologically inhibiting insulin receptor signaling in MHCI-deficient animals rescues synapse density, identifying insulin receptor signaling as a critical mediator of the tonic inhibitory effects of endogenous MHCI on synapse number. Insulin receptors co-immunoprecipitate MHCI from hippocampal lysates, and MHCI unmasks a cytoplasmic epitope of the insulin receptor that mediates downstream signaling. These results identify an important role for an MHCI–insulin receptor signaling pathway in circuit patterning in the developing brain, and suggest that changes in MHCI expression could unexpectedly regulate neuronal insulin sensitivity in the aging and diseased brain.