scholarly journals Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons

2013 ◽  
Vol 24 (16) ◽  
pp. 2494-2505 ◽  
Author(s):  
Elisa M. Ramser ◽  
Kathlyn J. Gan ◽  
Helena Decker ◽  
Emily Y. Fan ◽  
Matthew M. Suzuki ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Hippocampal Neurons ◽  
Glycogen Synthase ◽  
Amyloid Β ◽  
Protein Phosphatase 1 ◽  
Organelle Transport ◽  
Calcium Dependent ◽  
Pathological Event ◽  
Cultured Hippocampal Neurons

Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.

Role of GluN2A and GluN2B subunits in the formation of filopodia and secondary dendrites in cultured hippocampal neurons

2011 ◽  
Vol 385 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Frank Henle ◽  
Martina Dehmel ◽  
Jost Leemhuis ◽  
Catharina Fischer ◽  
Dieter K. Meyer
Keyword(s):  
Hippocampal Neurons ◽  
Cultured Hippocampal Neurons

Organelle motility and metabolism in axons vs dendrites of cultured hippocampal neurons

1996 ◽  
Vol 109 (5) ◽  
pp. 971-980 ◽  
Author(s):  
C.C. Overly ◽  
H.I. Rieff ◽  
P.J. Hollenbeck
Keyword(s):  
Regional Variation ◽  
Hippocampal Neurons ◽  
Retrograde Transport ◽  
Organelle Transport ◽  
Microtubule Polarity ◽  
Large Phase ◽  
Organelle Motility ◽  
The Difference ◽  
Metabolic Properties ◽  
Cultured Hippocampal Neurons

Regional regulation of organelle transport seems likely to play an important role in establishing and maintaining distinct axonal and dendritic domains in neurons, and in managing differences in local metabolic demands. In addition, known differences in microtubule polarity and organization between axons and dendrites along with the directional selectivity of microtubule-based motor proteins suggest that patterns of organelle transport may differ in these two process types. To test this hypothesis, we compared the patterns of movement of different organelle classes in axons and different dendritic regions of cultured embryonic rat hippocampal neurons. We first examined the net direction of organelle transport in axons, proximal dendrites and distal dendrites by video-enhanced phase-contrast microscopy. We found significant regional variation in the net transport of large phase-dense vesicular organelles: they exhibited net retrograde transport in axons and distal dendrites, whereas they moved equally in both directions in proximal dendrites. No significant regional variation was found in the net transport of mitochondria or macropinosomes. Analysis of individual organelle motility revealed three additional differences in organelle transport between the two process types. First, in addition to the difference in net transport direction, the large phase-dense organelles exhibited more persistent changes in direction in proximal dendrites where microtubule polarity is mixed than in axons where microtubule polarity is uniform. Second, while the net direction of mitochondrial transport was similar in both processes, twice as many mitochondria were motile in axons than in dendrites. Third, the mean excursion length of moving mitochondria was significantly longer in axons than in dendrites. To determine whether there were regional differences in metabolic activity that might account for these motility differences, we labeled mitochondria with the vital dye, JC-1, which reveals differences in mitochondrial transmembrane potential. Staining of neurons with this dye revealed a greater proportion of highly charged, more metabolically active, mitochondria in dendrites than in axons. Together, our data reveal differences in organelle motility and metabolic properties in axons and dendrites of cultured hippocampal neurons.

Role of Presynaptic L-Type Ca2+ Channels in GABAergic Synaptic Transmission in Cultured Hippocampal Neurons

1999 ◽  
Vol 81 (3) ◽  
pp. 1225-1230 ◽  
Author(s):  
Kimmo Jensen ◽  
Morten Skovgaard Jensen ◽  
John D. C. Lambert
Keyword(s):  
Synaptic Transmission ◽  
Transmitter Release ◽  
Hippocampal Neurons ◽  
Low Frequency ◽  
Tetanic Stimulation ◽  
Vesicle Release ◽  
Gabaergic Synaptic Transmission ◽  
Cultured Hippocampal Neurons ◽  
40 Hz

Role of presynaptic L-type Ca2+ channels in GABAergic synaptic transmission in cultured hippocampal neurons. Using dual whole cell patch-clamp recordings of monosynaptic GABAergic inhibitory postsynaptic currents (IPSCs) in cultured rat hippocampal neurons, we have previously demonstrated posttetanic potentiation (PTP) of IPSCs. Tetanic stimulation of the GABAergic neuron leads to accumulation of Ca2+ in the presynaptic terminals. This enhances the probability of GABA-vesicle release for up to 1 min, which underlies PTP. In the present study, we have examined the effect of altering the probability of release on PTP of IPSCs. Baclofen (10 μM), which depresses presynaptic Ca2+ entry through N- and P/Q-type voltage-dependent Ca2+ channels (VDCCs), caused a threefold greater enhancement of PTP than did reducing [Ca2+]o to 1.2 mM, which causes a nonspecific reduction in Ca2+ entry. This finding prompted us to investigate whether presynaptic L-type VDCCs contribute to the Ca2+ accumulation in the boutons during spike activity. The L-type VDCC antagonist, nifedipine (10 μM), had no effect on single IPSCs evoked at 0.2 Hz but reduced the PTP evoked by a train of 40 Hz for 2 s by 60%. Another L-type VDCC antagonist, isradipine (5 μM), similarly inhibited PTP by 65%. Both L-type VDCC blockers also depressed IPSCs during the stimulation (i.e., they increased tetanic depression). The L-type VDCC “agonist” (−)BayK 8644 (4 μM) had no effect on PTP evoked by a train of 40 Hz for 2 s, which probably saturated the PTP process, but enhanced PTP evoked by a train of 1 s by 91%. In conclusion, the results indicate that L-type VDCCs do not participate in low-frequency synchronous transmitter release, but contribute to presynaptic Ca2+ accumulation during high-frequency activity. This helps maintain vesicle release during tetanic stimulation and also enhances the probability of transmitter release during the posttetanic period, which is manifest as PTP. Involvement of L-type channels in these processes represents a novel presynaptic regulatory mechanism at fast CNS synapses.

scholarly journals L-type Ca2+ channel–mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions

2020 ◽  
Vol 13 (618) ◽  
pp. eaaw6923 ◽  
Author(s):  
Matej Hotka ◽  
Michal Cagalinec ◽  
Karlheinz Hilber ◽  
Livia Hool ◽  
Stefan Boehm ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Atp Synthase ◽  
Mitochondrial Function ◽  
Hippocampal Neurons ◽  
Mitochondrial Depolarization ◽  
Voltage Gated ◽  
Beneficial Effects ◽  
Reverse Mode ◽  
Cultured Hippocampal Neurons

L-type voltage-gated Ca2+ channels (LTCCs) are implicated in neurodegenerative processes and cell death. Accordingly, LTCC antagonists have been proposed to be neuroprotective, although this view is disputed, because intentional LTCC activation can also have beneficial effects. LTCC-mediated Ca2+ influx influences mitochondrial function, which plays a crucial role in the regulation of cell viability. Hence, we investigated the effect of modulating LTCC-mediated Ca2+ influx on mitochondrial function in cultured hippocampal neurons. To activate LTCCs, neuronal activity was stimulated by increasing extracellular K+ or by application of the GABAA receptor antagonist bicuculline. The activity of LTCCs was altered by application of an agonistic (Bay K8644) or an antagonistic (isradipine) dihydropyridine. Our results demonstrated that activation of LTCC-mediated Ca2+ influx affected mitochondrial function in a bimodal manner. At moderate stimulation strength, ATP synthase activity was enhanced, an effect that involved Ca2+-induced Ca2+ release from intracellular stores. In contrast, high LTCC-mediated Ca2+ loads led to a switch in ATP synthase activity to reverse-mode operation. This effect, which required nitric oxide, helped to prevent mitochondrial depolarization and sustained increases in mitochondrial Ca2+. Our findings indicate a complex role of LTCC-mediated Ca2+ influx in the tuning and maintenance of mitochondrial function. Therefore, the use of LTCC inhibitors to protect neurons from neurodegeneration should be reconsidered carefully.

Amyloid β-peptide(1–40)-mediated oxidative stress in cultured hippocampal neurons

1998 ◽  
Vol 10 (3) ◽  
pp. 181-192 ◽  
Author(s):  
Michael Y. Aksenov ◽  
Marina V. Aksenova ◽  
William R. Markesbery ◽  
D. Allan Butterfield
Keyword(s):  
Oxidative Stress ◽  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Cultured Hippocampal Neurons
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