Dendritic Arborization Patterns of Small Juxtaglomerular Cell Subtypes within the Rodent Olfactory Bulb.

Within the glomerular layer of the rodent olfactory bulb, numerous subtypes of local interneurons contribute to early processing of incoming sensory information. Here we have investigated dopaminergic and other small local juxtaglomerular cells in rats and mice and characterized their dendritic arborization pattern with respect to individual glomeruli by fluorescent labeling via patching and reconstruction of dendrites and glomerular contours from two-photon imaging data. Dopaminergic neurons were identified in a transgenic mouse line where the expression of dopamine transporter (DAT) was labeled with GFP. Among the DAT+ cells we found a small short-axon cell (SAC) subtype featuring hitherto undescribed dendritic specializations. These densely ramifying structures clasped mostly around somata of other juxtaglomerular neurons, which were also small, non-dopaminergic and to a large extent non-GABAergic. Clasping SACs were observed also in wild-type mice and juvenile rats. In DAT+ SAC dendrites, single backpropagating action potentials evoked robust calcium entry throughout both clasping and non-clasping compartments. Besides clasping SACs, most other small neurons either corresponded to the classical periglomerular cell type (PGCs), which was never DAT+, or were undersized cells with a small dendritic tree and low excitability. Aside from the presence of clasps in SAC dendrites, many descriptors of dendritic morphology such as the number of dendrites and the extent of branching were not significantly different between clasping SACs and PGCs. However, a detailed morphometric analysis in relation to glomerular contours revealed that the dendrites of clasping SACs arborized mostly in the juxtaglomerular space and never entered more than one glomerulus (if at all), whereas most PGC dendrites were restricted to their parent glomerulus, similar to the apical tufts of mitral cells. These complementary arborization patterns might underlie a highly complementary functional connectivity. The morphometric approach may serve to differentiate also other subtypes of juxtaglomerular neurons, help to identify putative synaptic partners and thus to establish a more refined picture of glomerular network interactions during odor sensing.

MRZ-99030 - A novel modulator of Aß aggregation: II - Reversal of Aß oligomer-induced deficits in long-term potentiation (LTP) and cognitive performance in rats and mice.

ß-amyloid1-42 (Aß1-42) is a major endogenous pathogen underlying the aetiology of Alzheimer's disease (AD). Recent evidence indicates that soluble Aß oligomers, rather than plaques, are the major cause of synaptic dysfunction and neurodegeneration. Small molecules that suppress Aß aggregation, reduce oligomer stability or promote off-pathway non-toxic oligomerization represent a promising alternative strategy for neuroprotection in AD. MRZ-99030 was recently identified as a dipeptide that modulates Aß1-42 aggregation by triggering a non-amyloidogenic aggregation pathway, thereby reducing the amount of intermediate toxic soluble oligomeric Aß species. The present study evaluated the relevance of these promising results with MRZ-99030 under pathophysiological conditions i.e. against the synaptotoxic effects of Aß oligomers on hippocampal long term potentiation (LTP) and two different memory tasks. Aß1-42 interferes with the glutamatergic system and with neuronal Ca(2+) signalling and abolishes the induction of LTP. Here we demonstrate that MRZ-99030 (100-500 nM) at a 10:1 stoichiometric excess to Aß clearly reversed the synaptotoxic effects of Aß1-42 oligomers on CA1-LTP in murine hippocampal slices. Co-application of MRZ-99030 also prevented the two-fold increase in resting Ca(2+) levels in pyramidal neuron dendrites and spines triggered by Aß1-42 oligomers. In anaesthetized rats, pre-administration of MRZ-99030 (50 mg/kg s.c.) protected against deficits in hippocampal LTP following i.c.v. injection of oligomeric Aß1-42. Furthermore, similar treatment significantly ameliorated cognitive deficits in an object recognition task and under an alternating lever cyclic ratio schedule after the i.c.v. application of Aß1-42 and 7PA2 conditioned medium, respectively. Altogether, these results demonstrate the potential therapeutic benefit of MRZ-99030 in AD.

Local postsynaptic voltage-gated sodium channel activation in dendritic spines of olfactory bulb granule cells.

Neuronal dendritic spines have been speculated to function as independent computational units, yet evidence for active electrical computation in spines is scarce. Here we show that strictly local voltage-gated sodium channel (Nav) activation can occur during excitatory postsynaptic potentials in the spines of olfactory bulb granule cells, which we mimic and detect via combined two-photon uncaging of glutamate and calcium imaging in conjunction with whole-cell recordings. We find that local Nav activation boosts calcium entry into spines through high-voltage-activated calcium channels and accelerates postsynaptic somatic depolarization, without affecting NMDA receptor-mediated signaling. Hence, Nav-mediated boosting promotes rapid output from the reciprocal granule cell spine onto the lateral mitral cell dendrite and thus can speed up recurrent inhibition. This striking example of electrical compartmentalization both adds to the understanding of olfactory network processing and broadens the general view of spine function.

The dual-oscillator system of Drosophila melanogaster under natural-like temperature cycles.

Dual-oscillator systems that control morning and evening activities can be found in a wide range of animals. The two coupled oscillators track dawn and dusk and flexibly adapt their phase relationship to seasonal changes. This is also true for the fruit fly Drosophila melanogaster that serves as model organism to understand the molecular and anatomical bases of the dual-oscillator system. In the present study, the authors investigated which temperature parameters are crucial for timing morning and evening activity peaks by applying natural-like temperature cycles with different daylengths. The authors found that the morning peak synchronizes to the temperature increase in the morning and the evening peak to the temperature decrease in the afternoon. The two peaks did not occur at fixed absolute temperatures, but responded flexibly to daylength and overall temperature level. Especially, the phase of the evening peak clearly depended on the absolute temperature level: it was delayed at high temperatures, whereas the phase of the M peak was less influenced. This suggests that the two oscillators have different temperature sensitivities. The bimodal activity rhythm was absent in the circadian clock mutants Clk(Jrk) and cyc(01) and reduced in per(01) and tim(01) mutants. Whereas the activity of Clk(Jrk) mutants just followed the temperature cycles, that of per(01) and tim(01) mutants did not, suggesting that these mutants are not completely clockless. This study revealed new characteristics of the dual-oscillator system in Drosophila that were not detected under different photoperiods.