Alterations in Piriform and Bulbar Activity/Excitability/Coupling Upon Amyloid-β Administration in vivo Related to Olfactory Dysfunction

2021 ◽  
pp. 1-17
Author(s):  
Ignacio Martínez-García ◽  
Rebeca Hernández-Soto ◽  
Benjamín Villasana-Salazar ◽  
Benito Ordaz ◽  
Fernando Peña-Ortega
Keyword(s):  
Piriform Cortex ◽  
Brain Slices ◽  
Amyloid Β ◽  
Olfactory Dysfunction ◽  
Network Activity ◽  
Pathological Changes ◽  
Olfactory Pathway ◽  
Lateral Olfactory Tract

Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro. Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro. Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.

scholarly journals Epileptiform Discharges With In-Vivo-Like Features in Slices of Rat Piriform Cortex With Longitudinal Association Fibers

2001 ◽  
Vol 86 (5) ◽  
pp. 2445-2460 ◽  
Author(s):  
Rezan Demir ◽  
Lewis B. Haberly ◽  
Meyer B. Jackson
Keyword(s):  
Seizure Activity ◽  
Epileptiform Activity ◽  
Piriform Cortex ◽  
Brain Slices ◽  
Epileptiform Discharges ◽  
Local Circuitry ◽  
Association Fibers ◽  
Discharge Propagation

Brain slices serve as useful models for the investigation of epilepsy. However, the preparation of brain slices disrupts circuitry and severs axons, thus complicating efforts to relate epileptiform activity in vitro to seizure activity in vivo. This issue is relevant to studies in transverse slices of the piriform cortex (PC), the preparation of which disrupts extensive rostrocaudal fiber systems. In these slices, epileptiform discharges propagate slowly and in a wavelike manner, whereas such discharges in vivo propagate more rapidly and jump abruptly between layers. The objective of the present study was to identify fiber systems responsible for these differences. PC slices were prepared by cutting along three different nearly orthogonal planes (transverse, parasagittal, and longitudinal), and epileptiform discharges were imaged with a voltage-sensitive fluorescent dye. Interictal-like epileptiform activity was enabled by either a kindling-like induction process or disinhibition with bicuculline. The pattern of discharge onset was very similar in slices cut in different planes. As described previously in transverse PC slices, discharges were initiated in the endopiriform nucleus (En) and adjoining regions in a two-stage process, starting with low-amplitude “plateau activity” at one site and leading to an accelerating depolarization and discharge onset at another nearby site. The similar pattern of onset in slices of various orientations indicates that the local circuitry and neuronal properties in and around the En, rather than long-range fibers, assume dominant roles in the initiation of epileptiform activity. Subtle variations in the onset site indicate that interneurons can fine tune the site of discharge onset. In contrast to the mode of onset, discharge propagation showed striking variations. In longitudinal slices, where rostrocaudal association fibers are best preserved, discharge propagation resembled in vivo seizure activity in the following respects: propagation was as rapid as in vivo and about two to three times faster than in other slices; discharges jumped abruptly between the En and PC; and discharges had large amplitudes in superficial layers of the PC. Cuts in longitudinal slices that partially separated the PC from the En eliminated these unique features. These results help clarify why epileptiform activity differs between in vitro and in vivo experiments and suggest that rostrocaudal pyramidal cell association fibers play a major role in the propagation of discharges in the intact brain. The longitudinal PC slice, which best preserves these fibers, is ideally suited for the study their role.

Duration of NMDA-Dependent Synaptic Potentiation in Piriform Cortex In Vivo Is Increased After Epileptiform Bursting

1998 ◽  
Vol 80 (4) ◽  
pp. 1623-1629 ◽  
Author(s):  
A. Kapur ◽  
L. B. Haberly
Keyword(s):  
Seizure Activity ◽  
Piriform Cortex ◽  
Long Term Potentiation ◽  
Excitatory Postsynaptic Potential ◽  
Synaptic Potentiation ◽  
Lateral Olfactory Tract ◽  
Afferent Fibers ◽  
Stimulation Of

Kapur, A. and L. B. Haberly. Duration of NMDA-dependent synaptic potentiation in piriform cortex in vivo is increased after epileptiform bursting. J. Neurophysiol. 80: 1623–1629, 1998. Stimulation of afferent fibers with current pulse trains has been reported to induce long-term potentiation (LTP) in piriform cortex in vitro but not in vivo. LTP has been observed in vivo only when trains are paired with behavioral reinforcement and as a consequence of kindled epileptogenesis. This study was undertaken in the urethan-anesthetized rat to determine if the reported failures to observe pulse-train evoked LTP in vivo may be related to a lesser persistence rather than lack of occurrence, if disinhibition might facilitate induction, and to examine the nature of the relationship between seizure activity and LTP. Stimulation of afferent fibers in the lateral olfactory tract with θ-burst trains under control conditions potentiated the monosynaptic field excitatory postsynaptic potential (EPSP) by approximately the same extent (20.3 ± 2%; n = 12) as reported for the slice. However, in contrast to the slice, potentiation in vivo decayed to a low level within 1–2 h after induction (70% loss in 1.5 h, on average). The N-methyl-d-aspartate (NMDA)-receptor antagonists d-APV and MK-801 blocked the induction of this decremental potentiation. Pharmacological reduction of γ-aminobutyric acid–mediated inhibition at the recording site did not increase the duration of potentiation. In contrast, θ-burst stimulation applied after recovery from a period of epileptiform bursting induced stable NMDA-dependent potentiation. Mean increase in the population EPSP was approximately the same as under control conditions (21 ± 2%; n = 6), but in five of six experiments there was little or no decay in potentiation for the duration of the monitoring period (≤6 h). It is concluded that seizure activity has an enabling action on the induction of persistent synaptic potentiation by stimulus trains that bypasses the need for behavioral reinforcement.

scholarly journals Intraneuronal chloride accumulation via NKCC1 is not essential for hippocampal network development in vivo

2020 ◽  
Author(s):  
Jürgen Graf ◽  
Chuanqiang Zhang ◽  
Stephan Lawrence Marguet ◽  
Tanja Herrmann ◽  
Tom Flossmann ◽  
...  
Keyword(s):  
Cognitive Abilities ◽  
Network Dynamics ◽  
Brain Slices ◽  
Network Activity ◽  
Long Term Effects ◽  
Network Function ◽  
Excitatory Gaba ◽  
A Minor

AbstractNKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in-vitro excitatory GABA actions and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics and behavioral performance are subtle. Our data reveal a neural network function of depolarizing GABA in the hippocampus in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

scholarly journals Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ernesto Flores-Martínez ◽  
Fernando Peña-Ortega
Keyword(s):  
Prefrontal Cortex ◽  
Brain Slices ◽  
Amyloid Β ◽  
Network Activity ◽  
Amyloid Β Peptide ◽  
Cell Level ◽  
Long Range Interactions ◽  
Induced Changes ◽  
The Brain

Alterations in prefrontal cortex (PFC) function and abnormalities in its interactions with other brain areas (i.e., the hippocampus) have been related to Alzheimer Disease (AD). Considering that these malfunctions correlate with the increase in the brain’s amyloid beta (Aβ) peptide production, here we looked for a causal relationship between these pathognomonic signs of AD. Thus, we tested whether or not Aβ affects the activity of the PFC network and the activation of this cortex by hippocampal input stimulation in vitro. We found that Aβ application to brain slices inhibits PFC spontaneous network activity as well as PFC activation, both at the population and at the single-cell level, when the hippocampal input is stimulated. Our data suggest that Aβ can contribute to AD by disrupting PFC activity and its long-range interactions throughout the brain.

scholarly journals A limited role of NKCC1 in telencephalic glutamatergic neurons for developing hippocampal network dynamics and behavior

2021 ◽  
Vol 118 (14) ◽  
pp. e2014784118
Author(s):  
Jürgen Graf ◽  
Chuanqiang Zhang ◽  
Stephan Lawrence Marguet ◽  
Tanja Herrmann ◽  
Tom Flossmann ◽  
...  
Keyword(s):  
Cognitive Abilities ◽  
Network Dynamics ◽  
Brain Slices ◽  
Network Activity ◽  
Long Term Effects ◽  
Network Function ◽  
Glutamatergic Neurons ◽  
A Minor

NKCC1 is the primary transporter mediating chloride uptake in immature principal neurons, but its role in the development of in vivo network dynamics and cognitive abilities remains unknown. Here, we address the function of NKCC1 in developing mice using electrophysiological, optical, and behavioral approaches. We report that NKCC1 deletion from telencephalic glutamatergic neurons decreases in vitro excitatory actions of γ-aminobutyric acid (GABA) and impairs neuronal synchrony in neonatal hippocampal brain slices. In vivo, it has a minor impact on correlated spontaneous activity in the hippocampus and does not affect network activity in the intact visual cortex. Moreover, long-term effects of the developmental NKCC1 deletion on synaptic maturation, network dynamics, and behavioral performance are subtle. Our data reveal a neural network function of NKCC1 in hippocampal glutamatergic neurons in vivo, but challenge the hypothesis that NKCC1 is essential for major aspects of hippocampal development.

Tolfenamic Acid Prevents Amyloid β-induced Olfactory Bulb Dysfunction In Vivo

2018 ◽  
Vol 15 (8) ◽  
pp. 731-742 ◽  
Author(s):  
José M. Cornejo-Montes-de-Oca ◽  
Rebeca Hernández-Soto ◽  
Arturo G. Isla ◽  
Carlos E. Morado-Urbina ◽  
Fernando Peña-Ortega
Keyword(s):  
Olfactory Bulb ◽  
Amyloid Beta ◽  
Amyloid Β ◽  
Tolfenamic Acid ◽  
Network Activity ◽  
Protective Effects ◽  
Population Activity ◽  
Activity Inhibition

Background: Amyloid beta inhibits olfactory bulb function. The mechanisms involved in this effect must include alterations in network excitability, inflammation and the activation of different transduction pathways. Thus, here we tested whether tolfenamic acid, a drug that modulates several of these pathological processes, could prevent amyloid beta-induced olfactory bulb dysfunction. Objective: To test whether tolfenamic acid prevents amyloid beta-induced alterations in olfactory bulb network function, olfaction and GSK3β activity. Method: The protective effects of tolfenamic acid against amyloid beta-induced population activity inhibition were tested in olfactory bulb slices from adult mice, while tolfenamic acid and amyloid beta were bath-applied. We also tested the effects of amyloid-beta in slices obtained from animals pre-treated chronically (21 days) with tolfenamic acid. The effects of amyloid beta micro-injected into the olfactory bulbs were also tested, after two weeks, on olfactory bulb population activity and olfaction in control and tolfenamic acid chronically treated animals. Olfaction was assessed with the odor-avoidance and the habituation/cross-habituation tests. GSK3β activation was evaluated with Western-blot. Results: Acute bath application of tolfenamic acid does not prevent amyloid beta-induced inhibition of olfactory bulb network activity in vitro. In contrast, chronic treatment with tolfenamic acid renders the olfactory bulb resistant to amyloid beta-induced network activity inhibition in vitro and in vivo, which correlates with the inhibition of GSK3β activation and the protection against amyloid beta-induced olfactory dysfunction. Conclusion: Our data further support the use of tolfenamic acid to prevent amyloid beta-induced pathology and the early symptoms of Alzheimer Disease.

scholarly journals Evaluation of in vitro neuronal networks for the study of spontaneous activity

STEMedicine ◽  
2020 ◽  
Vol 1 (2) ◽  
pp. e35 ◽  
Author(s):  
Diletta Pozzi
Keyword(s):  
Nervous System ◽  
Spontaneous Activity ◽  
Time Course ◽  
Neuronal Networks ◽  
Brain Slices ◽  
In Vitro Models ◽  
Network Activity ◽  
External Stimuli

In the absence of external stimuli, the nervous system exhibits a spontaneous electrical activity whose functions are not fully understood, and that represents the background noise of brain operations. Spontaneous activity has been proven to arise not only in vivo, but in in vitro neuronal networks as well, following some stereotypical patterns that reproduce the time course of development of the mammalian nervous system. This review provides an overview of in vitro models for the study of spontaneous network activity, discussing their ability to reproduce in vivo - like dynamics and the main findings obtained with each particular model. While explanted brain slices are able to reproduce the neuronal oscillations typically observed in anaesthetized animals, dissociated cultures allow the use of patient-derived neurons and limit the number of animals used for sample preparation.

scholarly journals Neurosteroids and Focal Epileptic Disorders

2020 ◽  
Vol 21 (24) ◽  
pp. 9391
Author(s):  
Maxime Lévesque ◽  
Giuseppe Biagini ◽  
Massimo Avoli
Keyword(s):  
Brain Slices ◽  
Mesial Temporal Lobe Epilepsy ◽  
Epileptic Activity ◽  
Network Activity ◽  
Interictal Spikes ◽  
In Vivo Models ◽  
High Frequency Oscillations ◽  
Spontaneous Seizures

Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids—allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)—are known to modulate GABAA receptor-mediated transmission, thus playing a role in controlling neuronal network excitability. Given the role of GABAA signaling in epileptic disorders, neurosteroids have profound effects on seizure generation and play a role in the development of chronic epileptic conditions (i.e., epileptogenesis). We review here studies showing the effects induced by neurosteroids on epileptiform synchronization in in vitro brain slices, on epileptic activity in in vivo models, i.e., in animals that were made epileptic with chemoconvulsant treatment, and in epileptic patients. These studies reveal that neurosteroids can modulate ictogenesis and the occurrence of pathological network activity such as interictal spikes and high-frequency oscillations (80–500 Hz). Moreover, they can delay the onset of spontaneous seizures in animal models of mesial temporal lobe epilepsy. Overall, this evidence suggests that neurosteroids represent a new target for the treatment of focal epileptic disorders.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

2021 ◽  
Author(s):  
Maryna Psol ◽  
Sofia Guerin Darvas ◽  
Kristian Leite ◽  
Sameehan U Mahajani ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Sporadic Case ◽  
Network Activity ◽  
Proteinase K ◽  
Neuronal Network Activity ◽  
Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

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