Perturbation of <i>in vivo</i> neural activity following α-Synuclein seeding in the olfactory bulb

Kulkarni, Aishwarya; Cortijo, María del Mar; Roberts, Elizabeth Rose; Suggs, Tamara L.; Stover, Heather B.; Pena-Bravo, José I.; Steiner, Jennifer A.; Luk, Kelvin C.; Brundin, Patrik; Wesson, Daniel W.

doi:10.1101/2020.04.17.045013

Cited by 3 publications

(10 citation statements)

References 80 publications

(113 reference statements)

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“…Taken together with recent work by Kulkarni et al [27], these results indicate that damage to the synapses between mitral and granule cells could be a potential mechanism (broadly speaking) for olfactory dysfunction in PD. More work needs to be done in looking at this increase in oscillatory power, and a computational model that includes beta oscillation needs to be implemented.…”

Section: Resultssupporting

confidence: 79%

“…This provides a testable marker that can help to identify potential network components damaged in PD. In fact, Kulkarni et al [27] recently recorded local field potentials in mice olfactory bulbs after injection of α-synuclein pre-formed fibrils. They saw a rise in oscillatory power during odor presentation after in incubation period ranging from 1-3 months post-injection.…”

Section: Discussionmentioning

confidence: 99%

“…They saw a rise in oscillatory power during odor presentation after in incubation period ranging from 1-3 months post-injection. This increase in oscillatory power was in the beta band only (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), while this network models activity in the gamma band (40-80 Hz), so comparison is limited. However, beta oscillations are likely mediated by the same synapses in the OB as gamma [57,58], and we believe these results to be related.…”

Section: Discussionmentioning

confidence: 99%

“…Oscillations in neural activity in the bulb may also play a part in encoding odor identity, and are likely important to odor recognition or information transfer, or both [21]. The precise manner in which PD impacts OB function is still a matter of investigation [26,27], although misfolded α-synuclein is present in the mitral, external tufted, granule, and periglomerular cells of PD patients [5,28,29].…”

Section: Introductionmentioning

confidence: 99%

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Increased oscillatory power in a computational model of the olfactory bulb due to synaptic degeneration

Berry

Cox

2020

Preprint

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The olfactory bulb (OB) is one of the first regions of the brain affected by Parkinson’s disease (PD) as measured by both dysfunction and presence of α-synuclein aggregation. Better understanding of how PD affects OB function could lead to earlier diagnosis and potential treatment. By simulating damage to the OB in a computational model, it may be possible to identify regions of interest or markers of early disease. We modified a simple rate-based computational model of the olfactory bulb and simulated damage to various components of the network. This was done for several configurations of the network, at different sizes and with 1D and 2D connectivity structures. We found that, in almost every case, activity of 2D networks were more robust to damage than 1D networks, leading us to conclude that a connection scheme of at least 2D is vital to computational modeling of the OB. We also found that certain types of damage (namely, seeded damage to the granule cell layer and to the synapses between mitral and granule cells) resulted in a peak of the oscillatory power of the network as a function of damage. This result is testable experimentally and bears further investigation utilizing more sophisticated computational models. If proven accurate, this rise in oscillatory power in the OB has the potential to be an early marker of PD.Author summaryOne of the first symptoms of Parkinson’s disease is the degradation of the sense of smell. The olfactory bulb is the first region of the brain to process odor information and is affected by Parkinson’s disease at early stages. We simulated neural activity in a computational model of the olfactory bulb in the presence of damage and compared it to simulations of undamaged activity. We found that 2D model networks were more robust to damage than their 1D counterparts. We also found that 2D networks displayed increased oscillatory activity when damage was applied to certain parts of the network. This last result, if proven correct, would potentially be a marker of early-stage Parkinson’s disease, and if so, could aid in early diagnosis and treatment of the disease.

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased oscillatory power in a computational model of the olfactory bulb due to synaptic degeneration

Berry

Cox

2020

Preprint

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“…Cortical network hyperactivity has been described in mouse models of AD and HD (Arnoux et al, 2018;Burgold et al, 2019;Busche et al, 2008;Liebscher et al, 2016;Marinković et al, 2019) and a recent study demonstrated spontaneous LFP elevations in the beta-and gammabands in the olfactory bulb and piriform cortex of mice observed in vivo after a-syn seeding (Kulkarni et al, 2020). Importantly, hyperactivation of sensorimotor cortical areas was also shown in electrophysiological and functional magnetic resonance imaging studies conducted in parkinsonian rats and patients and have been attributed to both motor and psychotic symptoms in synucleinopathies (Li et al, 2012;Nagahama et al, 2010;Yu et al, 2007).…”

Section: Discussionmentioning

confidence: 92%

Striatal seeding of protofibrillar alpha-synuclein causes cortical hyperreactivity in behaving mice

Blumenstock

Sun

Marinković

et al. 2020

Preprint

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SummaryAlpha-synucleinopathies are characterized by self-aggregation of the protein alpha-synuclein (a-syn), causing alterations on the molecular and cellular level. To unravel the impact of transneuronal spreading and templated misfolding of a-syn on the microcircuitry of remotely connected brain areas, we investigated cortical neuron function in awake mice 9 months after a single intrastriatal injection of a-syn preformed fibrils (PFFs), using in vivo two-photon calcium imaging. We found altered function of layer 2/3 cortical neurons in somatosensory cortex (S1) of PFF-inoculated mice, as witnessed by an enhanced response to whisking and increased synchrony, accompanied by a decrease in baseline Ca2+ levels. Stereological analyses revealed a reduction in GAD67-positive inhibitory cells in S1 in PFF-injected brains. These findings point to a disturbed excitation/inhibition balance as an important pathomechanism in alpha-synucleinopathies and demonstrate a clear association between the spread of toxic proteins and the initiation of altered neuronal function in remotely connected areas.

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Linking α-synuclein-induced synaptopathy and neural network dysfunction in early Parkinson’s disease

Kulkarni

Burns

Brundin

et al. 2022

Brain Communications

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The prodromal phase of Parkinson’s disease is characterized by aggregation of the misfolded pathogenic protein α-synuclein (α-syn) in select neural centers, co-occurring with non-motor symptoms including sensory and cognitive loss, and emotional disturbances. It is unclear whether neuronal loss is significant during the prodrome. Underlying these symptoms are synaptic impairments and aberrant neural network activity. However, the relationships between synaptic defects and network level perturbations are not established. In experimental models, pathological α-syn not only impacts neurotransmission at the synaptic level, but also leads to changes in brain network-level oscillatory dynamics – both of which likely contribute to non-motor deficits observed in Parkinson’s disease. Here we draw upon research from both human subjects and experimental models to propose a “synapse to network prodrome cascade” wherein prior to overt cell death, pathological α-syn induces synaptic loss and contributes to aberrant network activity which then gives rise to prodromal symptomology. As the disease progresses, abnormal patterns of neural activity ultimately lead to neuronal loss and clinical progression of disease. Finally, we outline goals and research needed to unravel the basis of functional impairments in Parkinson’s disease and other α-synucleinopathies.

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Perturbation of in vivo neural activity following α-Synuclein seeding in the olfactory bulb

Cited by 3 publications

References 80 publications

Increased oscillatory power in a computational model of the olfactory bulb due to synaptic degeneration

Increased oscillatory power in a computational model of the olfactory bulb due to synaptic degeneration

Striatal seeding of protofibrillar alpha-synuclein causes cortical hyperreactivity in behaving mice

Linking α-synuclein-induced synaptopathy and neural network dysfunction in early Parkinson’s disease

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