No abstract

Adult-born neurons continuously incorporate into the olfactory bulb where they rapidly establish contacts with a variety of synaptic inputs. Little is known, however, about the functional properties of their output. Characterization of synaptic outputs from new neurons is essential to assess the functional impact of adult neurogenesis on mature circuits. Here, we used optogenetics to control neurotransmitter release from new neurons. We found that light-induced synaptic GABA release from adult-born neurons leads to profound modifications of postsynaptic target firing patterns. We revealed that functional output synapses form just after new cells acquire the faculty to spike, but most synapses were made a month later. Despite discrepancies in the timing of new synapse recruitment, the properties of postsynaptic signals remain constant. Remarkably, we found that all major cell types of the olfactory bulb circuit, including output neurons and several distinct subtypes of local interneurons, were contacted by adult-born neurons. Thus, this study provides new insights into how new neurons integrate into the adult neural network and may influence the sense of smell.

width range, current steering, and other programmable features of the device. It is not possible to test all settings in a single programming visit, and more studies are needed to define the optimal parameter space for target signs.Another limitation was the lack of data on efficacy of chronic stimulation at a short pulse width. The participants were only exposed to each stimulation setting for a short time during a single programming visit; it is possible that long-term stimulation would have revealed differences between short and conventional pulse widths that were not apparent during the acute visit. However, the blinded assessment of motor signs (UPDRS III) during an acute stimulation challenge has previously been used as the primary efficacy endpoint in DBS studies [8][9][10] and reflected the chronic benefit of DBS.Despite these limitations, few controlled studies are aimed at achieving optimization of DBS programming, and this is the first double-blind assessment of the effect of a shorter pulse width and 1 of only a handful of DBS programming studies that have ever been conducted in a double-blind condition.In conclusion, stimulation using a shorter than currently recommended pulse width may be more efficient at achieving therapeutic efficacy and less likely to reach a side effect threshold. This may translate into a fundamentally new basic parameter setting for patients with DBS in PD. Supporting DataAdditional Supporting Information may be found in the online version of this article at the publisher's website. Short Pulse Width in AbstractBackground: We investigated the acute effect of short pulse widths on the therapeutic window in subthalamic nucleus deep brain stimulation in Parkinson's disease. Methods: We assessed 10 PD patients with STN-DBS at a 60-ms pulse width. We randomly and doubleblindedly applied 10-to 50-ms pulse widths. The principal outcome was the therapeutic window (difference --

Neuronal activity modulates the membrane diffusion of postsynaptic γ-aminobutyric acid (GABA)(A) receptors (GABA(A)Rs), thereby regulating the efficacy of GABAergic synapses. The K289M mutation in GABA(A)Rs subunit γ2 has been associated with the generalized epilepsy with febrile seizures plus (GEFS+) syndrome. This mutation accelerates receptor deactivation and therefore reduces inhibitory synaptic transmission. Yet, it is not clear why this mutation specifically promotes febrile seizures. We show that upon raising temperature both the number of GABA(A)Rs clusters and the frequency of miniature inhibitory postsynaptic currents decreased in neurons expressing the K289M mutant but not wild-type (WT) recombinant γ2. Single-particle tracking experiments revealed that raising temperature increases the membrane diffusion of synaptic GABA(A)Rs containing the K289M mutant but not WT recombinant γ2. This effect was mediated by enhanced neuronal activity as it was blocked by glutamate receptor antagonists and was mimicked by the convulsant 4-aminopyridine. Our data suggest the K289M mutation in γ2 confers GABA(A)Rs with enhanced sensitivity of their membrane diffusion to neuronal activity. Enhanced activity during hyperthermia may then trigger the escape of receptors from synapses and thereby further reduce the efficacy of GABAergic inhibition. Alteration of the membrane diffusion of neurotransmitter receptors therefore represents a new mechanism in human epilepsy.