scholarly journals Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis

2021 ◽  
Author(s):  
Bryan A Killinger ◽  
Patrik Brundin ◽  
Jeffery H Kordower ◽  
Gabriela Mercado ◽  
Solji G Choi ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Mitral Cell ◽  
Alpha Synuclein ◽  
Normal Function ◽  
Proteinase K ◽  
Mitral Cells ◽  
Cross Sectional ◽  
Lewy Pathology ◽  
Olfactory Tract ◽  
Healthy Humans

Synucleinopathies including Parkinsons disease and dementia with Lewy bodies are neurodegenerative diseases characterized by the intracellular accumulation of the protein alpha-synuclein called Lewy pathology. Alpha-synuclein within Lewy pathology is aggregated into protease resistant filamentous structures and is predominantly phosphorylated at serine 129 (PSER129). Lewy pathology has been hypothesized to spread throughout the nervous system as the disease progresses. Cross-sectional studies have shown the olfactory bulb and olfactory tract consistently bare LP for common synucleinopathies, making these structures likely starting points for the spreading process, and thus disease. Here we examined the distribution of PSER129 in non-diseased brain. To do this we used a sensitive tyramide signal amplification (TSA) technique to detect low abundance endogenous PSER129 under ideal antibody binding conditions. In wild-type non-diseased mice, PSER129 was detected in the olfactory bulb and several brain regions of the olfactory cortex across the neuroaxis (i.e., olfactory bulb to brain stem). PSER129 was particularly apparent in the mitral cell layer and the outer plexiform layer of the olfactory bulb where it was observed as cytosolic/nuclear puncta or fibers, respectively. PSER129 immunoreactivity in the healthy olfactory bulb was abolished by pretreatment of the tissue with proteinase K, pre-absorption of the primary antibody against the purified PSER129 peptide fragment, or the omission of the PSER129 antibody. Furthermore, PSER129 immunoreactivity was not observed in any brain region of alpha-synuclein knockout mice. Dual labeling for the PSER129 and the mitral cell marker TBX21 showed that PSER129 positive structures of the healthy OB were found in mitral cells. We found evidence of the same PSER129 positive structures in the olfactory bulb of non-diseased rats, non-human primates, healthy humans, but not individuals diagnosed with PD. Results suggest biological pathways responsible for alpha-synuclein phosphorylation are constitutively active in OB mitral cells and alpha-synuclein in these cells may be predisposed to pathological aggregation. Pathological seeds originating in mitral cells may act as a source for alpha-synuclein spread competent assemblies that spreads throughout the brain via fibers of the olfactory tract. Future studies should investigate the normal function of alpha-synuclein in the mitral cells of the olfactory bulb, which may give insight into synucleinopathy disease origins.

Group I Metabotropic Glutamate Receptors Are Differentially Expressed by Two Populations of Olfactory Bulb Granule Cells

2007 ◽  
Vol 97 (4) ◽  
pp. 3136-3141 ◽  
Author(s):  
Thomas Heinbockel ◽  
Kathryn A. Hamilton ◽  
Matthew Ennis
Keyword(s):  
Olfactory Bulb ◽  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Granule Cells ◽  
Mitral Cell ◽  
Mitral Cells ◽  
Patch Clamp Recording ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Bath Application

In the main olfactory bulb, several populations of granule cells (GCs) can be distinguished based on the soma location either superficially, interspersed with mitral cells within the mitral cell layer (MCL), or deeper, within the GC layer (GCL). Little is known about the physiological properties of superficial GCs (sGCs) versus deep GCs (dGCs). Here, we used patch-clamp recording methods to explore the role of Group I metabotropic glutamate receptors (mGluRs) in regulating the activity of GCs in slices from wildtype and mGluR−/− mutant mice. In wildtype mice, bath application of the selective Group I mGluR agonist DHPG depolarized and increased the firing rate of both GC subtypes. In the presence of blockers of fast synaptic transmission (APV, CNQX, gabazine), DHPG directly depolarized both GC subtypes, although the two GC subtypes responded differentially to DHPG in mGluR1−/− and mGluR5−/− mice. DHPG depolarized sGCs in slices from mGluR5−/− mice, although it had no effect on sGCs in slices from mGluR1−/− mice. By contrast, DHPG depolarized dGCs in slices from mGluR1−/− mice but had no effect on dGCs in slices from mGluR5−/− mice. Previous studies showed that mitral cells express mGluR1 but not mGluR5. The present results therefore suggest that sGCs are more similar to mitral cells than dGCs in terms of mGluR expression.

The Mitral and Short Axon Cells of the Olfactory Bulb

1970 ◽  
Vol 7 (3) ◽  
pp. 631-651
Author(s):  
J. L. PRICE ◽  
T. P. S. POWELL
Keyword(s):  
Electron Microscope ◽  
Olfactory Bulb ◽  
Granule Cells ◽  
Primary Dendrite ◽  
Plexiform Layer ◽  
Mitral Cell ◽  
Granule Cell Layer ◽  
Mitral Cells ◽  
Axon Initial Segments ◽  
Large Neurons

A description is given of the mitral and short axon cells of the olfactory bulb of the rat from Golgi material examined with the light microscope and from material examined with the electron microscope. The mitral cells are large neurons with primary and secondary dendrites which both extend into the overlying external plexiform layer, although only the primary dendrite enters the glomerular formations. No predominant antero-posterior orientation of the secondary dendrites has been found. Within the glomeruli the mitral cell dendrites are in synaptic contact with the olfactory nerves and also with the periglomerular cells, but elsewhere the only synapses on the mitral cells are the ‘reciprocal synapses’ with the granule cells. Synaptic-type vesicles are found in all parts of the mitral cells, including the axon initial segments; they appear to be especially concentrated in the distal portions of the dendrites. Several types of short axon cells have been found in the granule cell layer in Golgi-impregnated material. Their cell bodies can also be distinguished with the electron microscope, and from previous work it is probable that the axons of at least some of these cells form flattened-vesicle symmetrical synapses upon the granule cells.

Inhibition of Backpropagating Action Potentials in Mitral Cell Secondary Dendrites

2002 ◽  
Vol 88 (1) ◽  
pp. 64-85 ◽  
Author(s):  
Graeme Lowe
Keyword(s):  
Olfactory Bulb ◽  
Granule Cell ◽  
Action Potentials ◽  
Flash Photolysis ◽  
Glutamate Release ◽  
Mitral Cell ◽  
Repetitive Firing ◽  
Inhibitory Input ◽  
Mitral Cells ◽  
Distal Dendrite

The mammalian olfactory bulb is a geometrically organized signal-processing array that utilizes lateral inhibitory circuits to transform spatially patterned inputs. A major part of the lateral circuitry consists of extensively radiating secondary dendrites of mitral cells. These dendrites are bidirectional cables: they convey granule cell inhibitory input to the mitral soma, and they conduct backpropagating action potentials that trigger glutamate release at dendrodendritic synapses. This study examined how mitral cell firing is affected by inhibitory inputs at different distances along the secondary dendrite and what happens to backpropagating action potentials when they encounter inhibition. These are key questions for understanding the range and spatial dependence of lateral signaling between mitral cells. Backpropagating action potentials were monitored in vitro by simultaneous somatic and dendritic whole cell recording from individual mitral cells in rat olfactory bulb slices, and inhibition was applied focally to dendrites by laser flash photolysis of caged GABA (2.5-μm spot). Photolysis was calibrated to activate conductances similar in magnitude to GABAA-mediated inhibition from granule cell spines. Under somatic voltage-clamp with CsCl dialysis, uncaging GABA onto the soma, axon initial segment, primary and secondary dendrites evoked bicuculline-sensitive currents (up to −1.4 nA at −60 mV; reversal at ∼0 mV). The currents exhibited a patchy distribution along the axon and dendrites. In current-clamp recordings, repetitive firing driven by somatic current injection was blocked by uncaging GABA on the secondary dendrite ∼140 μm from the soma, and the blocking distance decreased with increasing current. In the secondary dendrites, backpropagated action potentials were measured 93–152 μm from the soma, where they were attenuated by a factor of 0.75 ± 0.07 (mean ± SD) and slightly broadened (1.19 ± 0.10), independent of activity (35–107 Hz). Uncaging GABA on the distal dendrite had little effect on somatic spikes but attenuated backpropagating action potentials by a factor of 0.68 ± 0.15 (0.45–0.60 μJ flash with 1-mM caged GABA); attenuation was localized to a zone of width 16.3 ± 4.2 μm around the point of GABA release. These results reveal the contrasting actions of inhibition at different locations along the dendrite: proximal inhibition blocks firing by shunting somatic current, whereas distal inhibition can impose spatial patterns of dendrodendritic transmission by locally attenuating backpropagating action potentials. The secondary dendrites are designed with a high safety factor for backpropagation, to facilitate reliable transmission of the outgoing spike-coded data stream, in parallel with the integration of inhibitory inputs.

scholarly journals Olfactory Nerve–Evoked, Metabotropic Glutamate Receptor–Mediated Synaptic Responses in Rat Olfactory Bulb Mitral Cells

2006 ◽  
Vol 95 (4) ◽  
pp. 2233-2241 ◽  
Author(s):  
Matthew Ennis ◽  
Mingyan Zhu ◽  
Thomas Heinbockel ◽  
Abdallah Hayar
Keyword(s):  
Olfactory Bulb ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Olfactory Nerve ◽  
Mitral Cell ◽  
Evoked Responses ◽  
Mitral Cells ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Apical Dendrites

The group I metabotropic glutamate receptor (mGluR) subtype, mGluR1, is highly expressed on the apical dendrites of olfactory bulb mitral cells and thus may be activated by glutamate released from olfactory nerve (ON) terminals. Previous studies have shown that mGluR1 agonists directly excite mitral cells. In the present study, we investigated the involvement of mGluR1 in ON-evoked responses in mitral cells in rat olfactory bulb slices using patch-clamp electrophysiology. In voltage-clamp recordings, the average EPSC evoked by single ON shocks or brief trains of ON stimulation (six pulses at 50 Hz) in normal physiological conditions were not significantly affected by the nonselective mGluR antagonist LY341495 (50–100 μΜ) or the mGluR1-specific antagonist LY367385 (100 μM); ON-evoked responses were attenuated, however, in a subset (36%) of cells. In the presence of blockers of ionotropic glutamate and GABA receptors, application of the glutamate uptake inhibitors THA (300 μM) and TBOA (100 μM) revealed large-amplitude, long-duration responses to ON stimulation, whereas responses elicited by antidromic activation of mitral/tufted cells were unaffected. Magnitudes of the ON-evoked responses elicited in the presence of THA–TBOA were dependent on stimulation intensity and frequency, and were maximal during high-frequency (50-Hz) bursts of ON spikes, which occur during odor stimulation. ON-evoked responses elicited in the presence of THA–TBOA were significantly reduced or completely blocked by LY341495 or LY367385 (100 μM). These results demonstrate that glutamate transporters tightly regulate access of synaptically evoked glutamate from ON terminals to postsynaptic mGluR1s on mitral cell apical dendrites. Taken together with other findings, the present results suggest that mGluR1s may not play a major role in phasic responses to ON input, but instead may play an important role in shaping slow oscillatory activity in mitral cells and/or activity-dependent regulation of plasticity at ON–mitral cell synapses.

scholarly journals Spontaneous activity generated within the olfactory bulb establishes the discrete wiring of mitral cell dendrites

2019 ◽  
Author(s):  
Satoshi Fujimoto ◽  
Marcus N. Leiwe ◽  
Richi Sakaguchi ◽  
Yuko Muroyama ◽  
Reiko Kobayakawa ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Spontaneous Activity ◽  
Neuronal Activity ◽  
Primary Dendrite ◽  
Sensory Information ◽  
Mitral Cell ◽  
Network Activity ◽  
Mitral Cells ◽  
Tufted Cells

ABSTRACTIn the mouse olfactory bulb, sensory information detected by ∼1,000 types of olfactory sensory neurons (OSNs) is represented by the glomerular map. The second-order neurons, mitral and tufted cells, connect a single primary dendrite to one glomerulus. This forms discrete connectivity between the ∼1,000 types of input and output neurons. It has remained unknown how this discrete dendrite wiring is established during development. We found that genetically silencing neuronal activity in mitral cells, but not from OSNs, perturbs the dendrite pruning of mitral cells. In vivo calcium imaging of awake neonatal animals revealed two types of spontaneous neuronal activity in mitral/tufted cells, but not in OSNs. Pharmacological and knockout experiments revealed a role for glutamate and NMDARs. The genetic blockade of neurotransmission among mitral/tufted cells reduced spontaneous activity and perturbed dendrite wiring. Thus, spontaneous network activity generated within the olfactory bulb self-organizes the parallel discrete connections in the mouse olfactory system.

scholarly journals BMPR-2 gates activity-dependent stabilization of dendrites during mitral cell remodeling

2020 ◽  
Author(s):  
Shuhei Aihara ◽  
Satoshi Fujimoto ◽  
Richi Sakaguchi ◽  
Takeshi Imai
Keyword(s):  
Olfactory Bulb ◽  
Neuronal Activity ◽  
Mitral Cell ◽  
In Utero ◽  
Mitral Cells ◽  
Selective Stabilization ◽  
Multiple Primary ◽  
Cell Remodeling ◽  
Developing Neurons ◽  
Activity Dependent

SUMMARYDeveloping neurons initially form excessive neurites and then remodel them based on molecular cues and neuronal activity. Developing mitral cells in the olfactory bulb initially extend multiple primary dendrites. They then stabilize single primary dendrites, while eliminating others. However, the mechanisms underlying the selective dendrite remodeling remain elusive. Using CRISPR/Cas9-based knockout screening combined with in utero electroporation, we identified BMPR-2 as a key regulator for the selective dendrite stabilization. Bmpr2 knockout and its rescue experiments show that BMPR-2 inhibits LIMK without ligands and thereby facilitates dendrite destabilization. In contrast, the overexpression of antagonists and agonists indicate that ligand-bound BMPR-2 stabilizes dendrites, most likely by releasing LIMK. Using genetic and FRET imaging experiments, we also demonstrate that free LIMK is activated by NMDARs via Rac1, facilitating dendrite stabilization through F-actin formation. Thus, the selective stabilization of mitral cell dendrites is ensured by concomitant inputs of BMP ligands and neuronal activity.

The Termination of Centrifugal Fibres in the Glomerular Layer of the Olfactory Bulb

1972 ◽  
Vol 10 (3) ◽  
pp. 621-635
Author(s):  
A. J. PINCHING ◽  
T. P. S. POWELL
Keyword(s):  
Electron Microscope ◽  
Olfactory Bulb ◽  
Mitral Cell ◽  
Lateral Olfactory Tract ◽  
Anterior Olfactory Nucleus ◽  
Axon Terminals ◽  
Glomerular Layer ◽  
Olfactory Tract ◽  
Functional Implications

The termination of the centrifugal fibres running in the lateral olfactory tract to the glomerular layer of the rat olfactory bulb has been determined with the electron microscope; this has been done with material perfused at various times after section of the lateral olfactory tract, as well as after a combination of this lesion with the long-term degeneration of olfactory nerves. The axon terminals are sparse at the glomerular level, but undergo typical degenerative changes; they are distributed solely in the periglomerular region and intermediate zone. The most common post-synaptic profiles are the processes of periglomerular cells, but a few centrifugal fibres terminate on short-axon, tufted and mitral cell dendrites. Evidence is produced to suggest that the anterior olfactory nucleus does not project as far as the glomerular layer. The findings are discussed in relation to previous studies with normal material and silver degeneration methods on similar experimental material; the functional implications of the centrifugal pathways in the bulb are briefly discussed.

SK Channel Regulation of Dendritic Excitability and Dendrodendritic Inhibition in the Olfactory Bulb

2005 ◽  
Vol 94 (6) ◽  
pp. 3743-3750 ◽  
Author(s):  
Brady J. Maher ◽  
Gary L. Westbrook
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Brain Slices ◽  
Mitral Cell ◽  
Mitral Cells ◽  
Sk Channels ◽  
Action Potential Firing ◽  
Sk Channel ◽  
Dendritic Excitability ◽  
Potential Firing

Small-conductance calcium-activated potassium channels (SK) regulate dendritic excitability in many neurons. In the olfactory bulb, regulation of backpropagating action potentials and dendrodendritic inhibition depend on the dendritic excitability of mitral cells. We report here that SK channel currents are present in mitral cells but are not detectable in granule cells in the olfactory bulb. In brain slices from PND 14–21 mice, long step depolarizations (100 ms) in the mitral cell soma evoked a cadmium- and apamin-sensitive outward SK current lasting several hundred milliseconds. Block of the SK current unmasked an inward N-methyl-d-aspartate (NMDA) autoreceptor current due to glutamate released from mitral cell dendrites. In low extracellular Mg2+ (100 μM), brief step depolarizations (2 ms) evoked an apamin-sensitive current that was reduced by d,l-2-amino-5-phosphonopentanoic acid. In current- clamp, block of SK channels increased action potential firing in mitral cells as well as dendrodendritic inhibition. Our results indicate that SK channels can be activated either by calcium channels or NMDA channels in mitral cell dendrites, providing a mechanism for local control of dendritic excitability.

Synaptic Organization and Neurotransmitters in the Rat Accessory Olfactory Bulb

1999 ◽  
Vol 81 (1) ◽  
pp. 345-355 ◽  
Author(s):  
Changping Jia ◽  
Wei R. Chen ◽  
Gordon M. Shepherd
Keyword(s):  
Olfactory Bulb ◽  
Granule Cells ◽  
Mitral Cell ◽  
Activity Period ◽  
Mitral Cells ◽  
Accessory Olfactory Bulb ◽  
Field Potentials ◽  
Synaptic Organization ◽  
Evoked Field Potentials ◽  
Stimulation Of

Jia, Changping, Wei R. Chen, and Gordon M. Shepherd. Synaptic organization and neurotransmitters in the rat accessory olfactory bulb. J. Neurophysiol. 81: 345–355, 1999. The accessory olfactory bulb (AOB) is the first relay station in the vomeronasal system and may play a critical role in processing pheromone signals. The AOB shows similar but less distinct lamination compared with the main olfactory bulb (MOB). In this study, synaptic organization of the AOB was analyzed in slice preparations from adult rats by using both field potential and patch-clamp recordings. Stimulation of the vomeronasal nerve (VN) evoked field potentials that showed characteristic patterns in different layers of the AOB. Current source density (CSD) analysis of the field potentials revealed spatiotemporally separated loci of inward current (sinks) that represented sequential activation of different neuronal components: VN activity (period I), synaptic excitation of mitral cell apical dendrites (period II), and activation of granule cells by mitral cell basal dendrites (period III). Stimulation of the lateral olfactory tract also evoked field potentials in the AOB, which indicated antidromic activation of the mitral cells (period I and II) followed by activation of granule cells (period III). Whole cell patch recordings from mitral and granule cells of the AOB supported that mitral cells are excited by VN terminals and subsequently activate granule cells through dendrodendritic synapses. Both CSD analysis and patch recordings provided evidence that glutamate is the neurotransmitter at the vomeronasal receptor neuron; mitral cell synapses and both NMDA and non-NMDA receptors are involved. We also demonstrated electrophysiologically that reciprocal interaction between mitral and granule cells in the AOB is through the dendrodendritic reciprocal synapses. The neurotransmitter at the mitral-to-granule synapses is glutamate and at the granule-to-mitral synapse is γ-aminobutyric acid. The synaptic interactions among receptor cell terminals, mitral cells, and granule cells in the AOB are therefore similar to those in the MOB, suggesting that processing of chemosensory information in the AOB shares similarities with that in the MOB.

scholarly journals Bursting mitral cells time the oscillatory coupling between olfactory bulb and entorhinal networks in neonatal mice

2020 ◽  
Author(s):  
Johanna K. Kostka ◽  
Sabine Gretenkord ◽  
Ileana L. Hanganu-Opatz
Keyword(s):  
Olfactory Bulb ◽  
Entorhinal Cortex ◽  
Mitral Cell ◽  
Network Activity ◽  
List Type ◽  
Mitral Cells ◽  
Early Postnatal Development ◽  
Theta Phase

ABSTRACTShortly after birth, the olfactory system provides to blind, deaf, non-whisking and motorically-limited rodents not only the main source of environmental inputs, but also the drive boosting the functional entrainment of limbic circuits. However, the cellular substrate of this early communication remains largely unknown. Here we combine in vivo and in vitro patch-clamp and extracellular recordings to reveal the contribution of mitral cell (MC) firing to the early patterns of network activity in the neonatal olfactory bulb (OB) and lateral entorhinal cortex (LEC), the gatekeeper of limbic circuits. We show that MCs predominantly fire either in an irregular bursting or non-bursting pattern during discontinuous theta events in OB. However, the temporal spike-theta phase coupling is stronger for bursting MCs when compared to non-bursting cells. In line with the direct OB projections to LEC, both bursting and non-bursting firing augments during coordinated patterns of entorhinal activity, yet to a higher magnitude for bursting MCs. These cells are stronger temporally coupled to the discontinuous theta events in LEC. Thus, bursting MCs might drive the entrainment of OB-LEC network during neonatal development.KEY POINTSDuring early postnatal development mitral cells show either irregular bursting or non-bursting firing patternsBursting mitral cells preferentially fire during theta bursts in the neonatal OB, being locked to the theta phaseBursting mitral cells preferentially fire during theta bursts in the neonatal lateral entorhinal cortex and are temporally related to both respiration rhythm- and theta phaseBursting mitral cells act as cellular substrate of the olfactory drive promoting the oscillatory entrainment of entorhinal networks

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