TY - JOUR AU - Timothy Browning ID - 253 IS - 1 JF - Mathematika TI - Counting rational points on cubic hypersurfaces: Corrigendum VL - 60 ER - TY - JOUR AB - The group III metabotropic glutamate (mGlu) receptors mGlu7 and mGlu8 are receiving increased attention as potential novel therapeutic targets for anxiety disorders. The effects mediated by these receptors appear to result from a complex interplay of facilitatory and inhibitory actions at different brain sites in the anxiety/fear circuits. To better understand the effect of mGlu7 and mGlu8 receptors on extinction of contextual fear and their critical sites of action in the fear networks, we focused on the amygdala. Direct injection into the basolateral complex of the amygdala of the mGlu7 receptor agonist AMN082 facilitated extinction, whereas the mGlu8 receptor agonist (S)-3,4-DCPG sustained freezing during the extinction acquisition trial. We also determined at the ultrastructural level the synaptic distribution of these receptors in the basal nucleus (BA) and intercalated cell clusters (ITCs) of the amygdala. Both areas are thought to exert key roles in fear extinction. We demonstrate that mGlu7 and mGlu8 receptors are located in different presynaptic terminals forming both asymmetric and symmetric synapses, and that they preferentially target neurons expressing mGlu1α receptors mostly located around ITCs. In addition we show that mGlu7 and mGlu8 receptors were segregated to different inputs to a significant extent. In particular, mGlu7a receptors were primarily onto glutamatergic afferents arising from the BA or midline thalamic nuclei, but not the medial prefrontal cortex (mPFC), as revealed by combined anterograde tracing and pre-embedding electron microscopy. On the other hand, mGlu8a showed a more restricted distribution in the BA and appeared absent from thalamic, mPFC and intrinsic inputs. This segregation of mGlu7 and mGlu8 receptors in different neuronal pathways of the fear circuit might explain the distinct effects on fear extinction training observed with mGlu7 and mGlu8 receptor agonists. AU - Dobi, Alice AU - Sartori, Simone B AU - Busti, Daniela AU - Van Der Putten, Herman V AU - Singewald, Nicolas AU - Ryuichi Shigemoto AU - Ferraguti, Francesco ID - 2692 JF - Neuropharmacology TI - Neural substrates for the distinct effects of presynaptic group III metabotropic glutamate receptors on extinction of contextual fear conditioning in mice VL - 66 ER - TY - JOUR AB - P/Q-type voltage-dependent calcium channels play key roles in transmitter release, integration of dendritic signals, generation of dendritic spikes, and gene expression. High intracellular calcium concentration transient produced by these channels is restricted to tens to hundreds of nanometers from the channels. Therefore, precise localization of these channels along the plasma membrane was long sought to decipher how each neuronal cell function is controlled. Here, we analyzed the distribution of Cav2.1 subunit of the P/Q-type channel using highly sensitive SDS-digested freeze-fracture replica labeling in the rat cerebellar Purkinje cells. The labeling efficiency was such that the number of immunogold particles in each parallel fiber active zone was comparable to that of functional channels calculated from previous reports. Two distinct patterns of Cav2.1 distribution, scattered and clustered, were found in Purkinje cells. The scattered Cav2.1 had a somatodendritic gradient with the density of immunogold particles increasing 2.5-fold from soma to distal dendrites. The other population with 74-fold higher density than the scattered particles was found within clusters of intramembrane particles on the P-face of soma and primary dendrites. Both populations of Cav2.1 were found as early as P3 and increased in the second postnatal week to a mature level. Using double immunogold labeling, we found that virtually all of the Cav2.1 clusters were colocalized with two types of calcium-activated potassium channels, BK and SK2, with the nearest neighbor distance of 40∼nm. Calcium nanodomain created by the opening of Cav2.1 channels likely activates the two channels that limit the extent of depolarization. AU - Indriati, Dwi Wahyu AU - Kamasawa, Naomi AU - Matsui, Ko AU - Meredith, Andrea L AU - Watanabe, Masahiko AU - Ryuichi Shigemoto ID - 2691 IS - 8 JF - Journal of Neuroscience TI - Quantitative localization of Cav2.1 (P/Q-Type) voltage-dependent calcium channels in Purkinje cells: Somatodendritic gradient and distinct somatic coclustering with calcium-activated potassium channels VL - 33 ER - TY - JOUR AB - Establishing the spatiotemporal concentration profile of neurotransmitter following synaptic vesicular release is essential for our understanding of inter-neuronal communication. Such profile is a determinant of synaptic strength, short-term plasticity and inter-synaptic crosstalk. Synaptically released glutamate has been suggested to reach a few millimolar in concentration and last for <1 ms. The synaptic cleft is often conceived as a single concentration compartment, whereas a huge gradient likely exists. Modelling studies have attempted to describe this gradient, but two key parameters, the number of glutamate in a vesicle (NGlu) and its diffusion coefficient (DGlu) in the extracellular space, remained unresolved. To determine this profile, the rat calyx of Held synapse at postnatal day 12-16 was studied where diffusion of glutamate occurs two-dimensionally and where quantification of AMPA receptor distribution on individual postsynaptic specialization on medial nucleus of the trapezoid body principal cells is possible using SDS-digested freeze-fracture replica labelling. To assess the performance of these receptors as glutamate sensors, a kinetic model of the receptors was constructed from outside-out patch recordings. From here, we simulated synaptic responses and compared them with the EPSC recordings. Combinations of NGlu and DGlu with an optimum of 7000 and 0.3 μm2 ms-1 reproduced the data, suggesting slow diffusion. Further simulations showed that a single vesicle does not saturate the synaptic receptors, and that glutamate spillover does not affect the conductance amplitude at this synapse. Using the estimated profile, we also evaluated how the number of multiple vesicle releases at individual active zones affects the amplitude of postsynaptic signals. AU - Budisantoso, Timotheus AU - Harumi Harada AU - Kamasawa, Naomi AU - Fukazawa, Yugo AU - Ryuichi Shigemoto AU - Matsui, Ko ID - 2690 IS - 1 JF - Journal of Physiology TI - Evaluation of glutamate concentration transient in the synaptic cleft of the rat calyx of Held VL - 591 ER - TY - JOUR AB - Inhibitory parvalbumin-containing interneurons (PVIs) control neuronal discharge and support the generation of theta- and gammafrequency oscillations in cortical networks. Fast GABAergic input onto PVIs is crucial for their synchronization and oscillatory entrainment, but the role of metabotropic GABAB receptors (GABABRs) in mediating slow presynaptic and postsynaptic inhibition remains unknown. In this study, we have combined high-resolution immunoelectron microscopy, whole-cell patch-clamp recording, and computational modeling to investigate the subcellular distribution and effects of GABABRs and their postsynaptic effector Kir3 channels in rat hippocampal PVIs. Pre-embedding immunogold labeling revealed that the receptors and channels localize at high levels to the extrasynaptic membrane of parvalbumin-immunoreactive dendrites. Immunoreactivity forGABABRs was also present at lower levels on PVI axon terminals. Whole-cell recordings further showed that synaptically released GABA in response to extracellular stimulation evokes large GABABR-mediated slow IPSCs in perisomatic-targeting (PT) PVIs, but only small or no currents in dendrite-targeting (DT) PVIs. In contrast, paired recordings demonstrated that GABABR activation results in presynaptic inhibition at the output synapses of both PT and DT PVIs, but more strongly in the latter. Finally, computational analysis indicated that GABAB IPSCs can phasically modulate the discharge of PT interneurons at theta frequencies. In summary, our results show that GABABRs differentially mediate slow presynaptic and postsynaptic inhibition in PVIs and can contribute to the dynamic modulation of their activity during oscillations. Furthermore, these data provide evidence for a compartment-specific molecular divergence of hippocampal PVI subtypes, suggesting that activation of GABABRs may shift the balance between perisomatic and dendritic inhibition. AU - Booker, Sam A AU - Gross, Anna AU - Althof, Daniel AU - Ryuichi Shigemoto AU - Bettler, Bernhard AU - Frotscher, Michael AU - Hearing, Matthew C AU - Wickman, Kevin D AU - Watanabe, Masahiko AU - Kulik, Ákos AU - Vida, Imre ID - 2693 IS - 18 JF - Journal of Neuroscience TI - Differential GABAB-receptor-mediated effects in perisomatic- and dendrite-targeting parvalbumin interneurons VL - 33 ER - TY - JOUR AB - We consider non-interacting particles subject to a fixed external potential V and a self-generated magnetic field B. The total energy includes the field energy β∫B2 and we minimize over all particle states and magnetic fields. In the case of spin-1/2 particles this minimization leads to the coupled Maxwell-Pauli system. The parameter β tunes the coupling strength between the field and the particles and it effectively determines the strength of the field. We investigate the stability and the semiclassical asymptotics, h→0, of the total ground state energy E(β,h,V). The relevant parameter measuring the field strength in the semiclassical limit is κ=βh. We are not able to give the exact leading order semiclassical asymptotics uniformly in κ or even for fixed κ. We do however give upper and lower bounds on E with almost matching dependence on κ. In the simultaneous limit h→0 and κ→∞ we show that the standard non-magnetic Weyl asymptotics holds. The same result also holds for the spinless case, i.e. where the Pauli operator is replaced by the Schrödinger operator. AU - Erdös, László AU - Fournais, Søren AU - Solovej, Jan ID - 2698 IS - 6 JF - Journal of the European Mathematical Society TI - Stability and semiclassics in self-generated fields VL - 15 ER - TY - JOUR AB - We consider Hermitian and symmetric random band matrices H = (h xy ) in d⩾1 d ⩾ 1 dimensions. The matrix entries h xy , indexed by x,y∈(Z/LZ)d x , y ∈ ( Z / L Z ) d , are independent, centred random variables with variances sxy=E|hxy|2 s x y = E | h x y | 2 . We assume that s xy is negligible if |x − y| exceeds the band width W. In one dimension we prove that the eigenvectors of H are delocalized if W≫L4/5 W ≫ L 4 / 5 . We also show that the magnitude of the matrix entries |Gxy|2 | G x y | 2 of the resolvent G=G(z)=(H−z)−1 G = G ( z ) = ( H - z ) - 1 is self-averaging and we compute E|Gxy|2 E | G x y | 2 . We show that, as L→∞ L → ∞ and W≫L4/5 W ≫ L 4 / 5 , the behaviour of E|Gxy|2 E | G x y | 2 is governed by a diffusion operator whose diffusion constant we compute. Similar results are obtained in higher dimensions. AU - László Erdös AU - Knowles, Antti AU - Yau, Horng-Tzer AU - Yin, Jun ID - 2697 IS - 1 JF - Communications in Mathematical Physics TI - Delocalization and diffusion profile for random band matrices VL - 323 ER - TY - CONF AB - Even though both population and quantitative genetics, and evolutionary computation, deal with the same questions, they have developed largely independently of each other. I review key results from each field, emphasising those that apply independently of the (usually unknown) relation between genotype and phenotype. The infinitesimal model provides a simple framework for predicting the response of complex traits to selection, which in biology has proved remarkably successful. This allows one to choose the schedule of population sizes and selection intensities that will maximise the response to selection, given that the total number of individuals realised, C = ∑t Nt, is constrained. This argument shows that for an additive trait (i.e., determined by the sum of effects of the genes), the optimum population size and the maximum possible response (i.e., the total change in trait mean) are both proportional to √C. AU - Barton, Nicholas H AU - Paixao, Tiago ID - 2718 T2 - Proceedings of the 15th annual conference on Genetic and evolutionary computation TI - Can quantitative and population genetics help us understand evolutionary computation? ER - TY - JOUR AB - Knowledge of the rate and fitness effects of mutations is essential for understanding the process of evolution. Mutations are inherently difficult to study because they are rare and are frequently eliminated by natural selection. In the ciliate Tetrahymena thermophila, mutations can accumulate in the germline genome without being exposed to selection. We have conducted a mutation accumulation (MA) experiment in this species. Assuming that all mutations are deleterious and have the same effect, we estimate that the deleterious mutation rate per haploid germline genome per generation is U = 0.0047 (95% credible interval: 0.0015, 0.0125), and that germline mutations decrease fitness by s = 11% when expressed in a homozygous state (95% CI: 4.4%, 27%). We also estimate that deleterious mutations are partially recessive on average (h = 0.26; 95% CI: –0.022, 0.62) and that the rate of lethal mutations is <10% of the deleterious mutation rate. Comparisons between the observed evolutionary responses in the germline and somatic genomes and the results from individual-based simulations of MA suggest that the two genomes have similar mutational parameters. These are the first estimates of the deleterious mutation rate and fitness effects from the eukaryotic supergroup Chromalveolata and are within the range of those of other eukaryotes. AU - Long, Hongan AU - Paixao, Tiago AU - Azevedo, Ricardo AU - Zufall, Rebecca ID - 2720 IS - 2 JF - Genetics TI - Accumulation of spontaneous mutations in the ciliate Tetrahymena thermophila VL - 195 ER - TY - CONF AB - Prediction of the evolutionary process is a long standing problem both in the theory of evolutionary biology and evolutionary computation (EC). It has long been realized that heritable variation is crucial to both the response to selection and the success of genetic algorithms. However, not all variation contributes in the same way to the response. Quantitative genetics has developed a large body of work trying to estimate and understand how different components of the variance in fitness in the population contribute to the response to selection. We illustrate how to apply some concepts of quantitative genetics to the analysis of genetic algorithms. In particular, we derive estimates for the short term prediction of the response to selection and we use variance decomposition to gain insight on local aspects of the landscape. Finally, we propose a new population based genetic algorithm that uses these methods to improve its operation. AU - Paixao, Tiago AU - Barton, Nicholas H ID - 2719 T2 - Proceedings of the 15th annual conference on Genetic and evolutionary computation TI - A variance decomposition approach to the analysis of genetic algorithms ER -