Dendritic-cell vaccines on the move

Abstract

create a hybrid tool that might have enhanced power and a broader ability to reverse harmful neuronal activity in pathological conditions. Creed and colleagues set out to investigate this possibility using a mouse model of cocaine addiction. In these mice, cocaine is injected directly into different parts of a brain region called the nucleus accumbens (NAc), inducing long-term neuronal depression or potentiation (a decrease or increase, respectively , in the responsiveness of neurons to incoming neural impulses). This alters transmission across the synaptic junctions of NAc neurons and thus specifically alters motor behaviour-a well-known effect of cocaine addiction. Previous work shows that DBS in the NAc has only a transient effect on addic-tive behaviour in this mouse model, but there is evidence that optogenetic stimulation of the metabotropic glutamate receptor protein (mGluR) has a longer-lasting effect. Opto-genetic activation of mGluR restores normal synaptic transmission and erases addiction behaviours by depressing the activity of a popu lation of NAc neurons that express the D1 dopamine-receptor protein and show increased activity in response to cocaine addiction. The authors confirmed this optogenetic effect, and used the biological basis of the technique to try to determine how DBS could be modified, refined or combined with drugs to improve its effectiveness. They manipulated the parameters of DBS, using HFS or LFS, in the core or in the shell of the NAc (its two subregions), and with or without injection of D1-receptor antagonists into the NAc. They discovered that when acute LFS was refined by inhibiting D1 receptors , the response mimicked optogenetic mGluR-dependent restoration of synaptic transmission, and had a long-lasting ability to abolish addictive behaviours. The authors conclude that approaches such as this, which combine two treatments, might open up new therapeutic avenues. But such combination studies are somewhat difficult to interpret, in part because of the different spatial scales over which each technique acts. Optogenetics is focal and specifically acts only on chosen neurons, but DBS, at whatever frequency, acts on larger regions and activates both excitatory and inhibitory neurons indiscriminately 8. The authors predict that tailoring DBS by taking inspiration from optogenetics might lead to long-lasting, if not permanent, treatments. This would be a major improvement , and would increase its range of applications. Furthermore, the study's results point to other ways of treating patients with cocaine addiction or other pathological conditions-systemic administration of D1-receptor antagonists, for instance, or the use of 'double-channel' strategies that involve targeted delivery of both DBS and pharmacological agents (or optogenetically activated proteins) to the same brain region or to two different sites. Achieving these improvements will not be straightforward. Sophisticated techniques will be required to achieve optogenetic or pharmacological modification of human synapses. If the effects are not permanent, strategies must be developed to enable the repeated introduction of drugs or genetic constructs to the appropriate brain region. Furthermore, treatment of some behaviours might require DBS or combination therapies at more than one site, or over large regions. Such advances might become possible through the development of nanotechnologies 9. It is difficult to analyse different complex effects in a tiny region of the mouse brain and extend those findings to humans. This is why optogenetics, for the time being, remains at the periphery of human therapeutic applications. The possibilities opened up by Creed and colleagues' study might help us to cross this frontier. ■