Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption.

The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system

Structural and Functional Characterization of the Interaction of Snapin with the Dopamine Transporter: Differential Modulation of Psychostimulant Actions

International audienceThe importance of dopamine (DA) neurotransmission is emphasized by its direct implication in several neurological and psychiatric disorders. The DA transporter (DAT), target of psychostimulant drugs, is the key protein that regulates spatial and temporal activity of DA in the synaptic cleft via the rapid reuptake of DA into the presynaptic terminal. There is strong evidence suggesting that DAT-interacting proteins may have a role in its function and regulation. Performing a two-hybrid screening, we identified snapin, a SNARE-associated protein implicated in synaptic transmission, as a new binding partner of the carboxyl terminal of DAT. Our data show that snapin is a direct partner and regulator of DAT. First, we determined the domains required for this interaction in both proteins and characterized the DAT-snapin interface by generating a 3D model. Using different approaches, we demonstrated that (i) snapin is expressed in vivo in dopaminergic neurons along with DAT; (ii) both proteins colocalize in cultured cells and brain and, (iii) DAT and snapin are present in the same protein complex. Moreover, by functional studies we showed that snapin produces a significant decrease in DAT uptake activity. Finally, snapin downregulation in mice produces an increase in DAT levels and transport activity, hence increasing DA concentration and locomotor response to amphetamine. In conclusion, snapin/DAT interaction represents a direct link between exocytotic and reuptake mechanisms and is a potential target for DA transmission modulation

Antidepressive effects of targeting ELK-1 signal transduction

International audienceDepression, a devastating psychiatric disorder, is a leadingcause of disability worldwide. Current antidepressants addressspecific symptoms of the disease, but there is vast roomfor improvement1. In this respect, new compounds that actbeyond classical antidepressants to target signal transductionpathways governing synaptic plasticity and cellular resilienceare highly warranted2–4. The extracellular signal–regulatedkinase (ERK) pathway is implicated in mood regulation5–7, butits pleiotropic functions and lack of target specificity prohibitoptimal drug development. Here, we identified the transcriptionfactor ELK-1, an ERK downstream partner8, as a specificsignaling module in the pathophysiology and treatment ofdepression that can be targeted independently of ERK. ELK1mRNA was upregulated in postmortem hippocampal tissuesfrom depressed suicides; in blood samples from depressedindividuals, failure to reduce ELK1 expression was associatedwith resistance to treatment. In mice, hippocampal ELK-1 overexpressionper se produced depressive behaviors; conversely,the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states inducedby stress. Our work stresses the importance of target selectivityfor a successful approach for signal-transduction-basedantidepressants, singles out ELK-1 as a depression-relevanttransducer downstream of ERK and brings proof-of-conceptevidence for the druggability of ELK-1