It is well known that the cause of some familial cases of frontotemporal dementia (FTD) is the presence of single mutations in the MAPT gene that codes for the tau protein. Mutated (pathological) tau initiates the disease but the mechanisms for the consecutive steps are not yet well defined.
In this work by Stern’s group, the authors clearly show that mutated tau disrupts ongoing cortical network activity that may result in cognitive deficits. Looking at neocortical activity in an FTD mouse model (expressing human tau with an FTD-mutation), they found that the membrane potential oscillations (MPOs) derived from neurons were slower than MPOs derived from wild-type mice. This result, and other conclusions of the paper, clearly demonstrates that pathological tau could reduce the activity of single neocortical cells.
The study reports an original observation, suggesting a novel function for tau. However, to extrapolate these results to the possible dysfunctions occurring in people with FTD, we should take into account the level of the mutated tau needed to promote the dysfunction. In other words, in the model we do not have only the effect of a toxic agent but, probably, the effect of a higher concentration of that toxic agent than that occurring in FTD. We do not know the level of toxic agent that is necessary to have that toxic effect. Indeed, it is not easy to compare human tau expression in the mouse model, with that occurring in specific neurons in the brain of a patient with dementia.
Zuzana Siskova Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), AG Mandelkow
Posted:
In this elegant study, Menkes-Caspi et al. provide a comprehensive insight into the dynamics of neocortical networks and activity of single neocortical pyramidal neurons in the rTg4510 mouse model of tauopathy. Using intracellular and extracellular recordings in anesthetized and freely moving animals at two stages (3- to 3.5-month-old animals and 4.5- to 6-month-old animals), they showed that spontaneous, ongoing, neocortical activity was disrupted during various arousal states and that firing rates of transgenic neurons were significantly reduced.
The main findings include slower membrane potential oscillations during slow-wave sleep and under anaesthesia in the transgenic mice. The authors postulate (based on their intracellular recordings in anesthetized animals) that these changes may occur due to longer "down" states and state transitions of membrane potentials. The nature of these findings is not completely clear. One important point to consider may be the temperature-related effects of anaesthesia that ultimately lead to increased phosphorylation of tau via a signalling cascade that is sensitive to the body temperature drop by only a few degrees (Planel et al., 2008). It is not clear how the increase in tau phosphorylation may translate into the patterns of neuronal firing and sub-threshold membrane potential dynamics during intracellular recordings in the present study, but it may render tau mice more susceptible to the effects. Thus, the article prompts more experiments on non-anesthetized animals to clarify this. In the present study, intracellular and extracellular recordings were performed in separate experiments. While this design does not undermine the conclusions, it would be insightful to study the unitary, cellular, and network activities during simultaneous recordings.
The study also found that neocortical activity was globally reduced to a greater degree in older animals with higher levels of neurofibrillary tangles; however, the activity was also reduced in neurons without detectable levels of pathological tau. The authors propose that the effects of pathological tau on a fraction of neurons may further amplify and spread throughout the entire cortical network. This would imply that a neuron may receive the adverse effects indirectly from the other affected neurons and in the absence of pathological tau. This mechanism may have broader implications for other neurological diseases associated with misfolding and aggregation of toxic proteins. However, it remains to be determined whether the findings can be explained by soluble tau (elevated at this stage), or even pathological tau that falls below the detection threshold of commonly used techniques, as suggested by the authors and others (Oh et al., 2010). In short, the paper prompts more studies to improve the detection methods routinely used in the field.
Previous studies of the rTg4510 model have also reported that structural and functional changes in layer III frontal cortical pyramidal neurons were not associated with the presence of neurofibrillary tangles, even in mice 8.5- to 9.5-months of age (Rocher et al., 2010; Crimins et al., 2011). Rigorous in vitro studies have also demonstrated that increased excitability and higher action potential firing rates (attributed to depolarized resting membrane potential) were typical for neurons of tau mice, in contrast to the present in vivo findings (Rocher et al., 2010). This discrepancy between in vivo and in vitro results may be due to the inherent differences between preparation and recording techniques (as stated by the authors) or to age-related differences. Further in vivo studies are needed. In APP/PS1 mice, for example, intracellular recordings of hippocampal CA1 neurons at late-stage disease (10 to 14 months of age) reveal elevated firing rates and frequent occurrence of action potential bursts in vivo that are confirmed by recordings in slices (Šišková et al., 2014). In the rTg4510 model it would have been interesting to compare the outcomes of slice recordings reported by Menkes-Caspi et al. with previous studies of the rTg4510 model.
The relationship between tau and another neurotoxic protein, Aβ, has been studied extensively by others in the field. One study has observed that reducing tau levels ameliorates spontaneous epileptiform activity and also the severity of spontaneous and induced seizures in several transgenic mouse lines overexpressing human amyloid precursor protein. Following tau reduction, inhibitory currents recorded in acute hippocampal slices were increased and the balance between excitation and inhibition was restored (Roberson et al., 2011).
More comprehensive studies using powerful experimental approaches, such as included in the current work, will be required to finally dissect out the mechanisms underlying neuronal and brain network abnormalities induced by the interactions of several toxic proteins in individuals with Alzheimer’s disease and other neurological conditions.
References:
Crimins JL, Rocher AB, Peters A, Shultz P, Lewis J, Luebke JI.
Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy.
Acta Neuropathol. 2011 Nov;122(5):551-64.
PubMed.
Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ.
Staging of Alzheimer's pathology in triple transgenic mice: a light and electron microscopic analysis.
Int J Alzheimers Dis. 2010;2010
PubMed.
Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE.
Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo.
J Neurosci. 2008 Nov 26;28(48):12798-807.
PubMed.
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L.
Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
J Neurosci. 2011 Jan 12;31(2):700-11.
PubMed.
Rocher AB, Crimins JL, Amatrudo JM, Kinson MS, Todd-Brown MA, Lewis J, Luebke JI.
Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs.
Exp Neurol. 2010 Jun;223(2):385-93.
PubMed.
Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T, Pitsch J, Schoch S, Becker A, von der Kammer H, Remy S.
Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease.
Neuron. 2014 Dec 3;84(5):1023-33. Epub 2014 Nov 13
PubMed.
Comments
Universidad Autónoma de Madrid
It is well known that the cause of some familial cases of frontotemporal dementia (FTD) is the presence of single mutations in the MAPT gene that codes for the tau protein. Mutated (pathological) tau initiates the disease but the mechanisms for the consecutive steps are not yet well defined.
In this work by Stern’s group, the authors clearly show that mutated tau disrupts ongoing cortical network activity that may result in cognitive deficits. Looking at neocortical activity in an FTD mouse model (expressing human tau with an FTD-mutation), they found that the membrane potential oscillations (MPOs) derived from neurons were slower than MPOs derived from wild-type mice. This result, and other conclusions of the paper, clearly demonstrates that pathological tau could reduce the activity of single neocortical cells.
The study reports an original observation, suggesting a novel function for tau. However, to extrapolate these results to the possible dysfunctions occurring in people with FTD, we should take into account the level of the mutated tau needed to promote the dysfunction. In other words, in the model we do not have only the effect of a toxic agent but, probably, the effect of a higher concentration of that toxic agent than that occurring in FTD. We do not know the level of toxic agent that is necessary to have that toxic effect. Indeed, it is not easy to compare human tau expression in the mouse model, with that occurring in specific neurons in the brain of a patient with dementia.
Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), AG Mandelkow
In this elegant study, Menkes-Caspi et al. provide a comprehensive insight into the dynamics of neocortical networks and activity of single neocortical pyramidal neurons in the rTg4510 mouse model of tauopathy. Using intracellular and extracellular recordings in anesthetized and freely moving animals at two stages (3- to 3.5-month-old animals and 4.5- to 6-month-old animals), they showed that spontaneous, ongoing, neocortical activity was disrupted during various arousal states and that firing rates of transgenic neurons were significantly reduced.
The main findings include slower membrane potential oscillations during slow-wave sleep and under anaesthesia in the transgenic mice. The authors postulate (based on their intracellular recordings in anesthetized animals) that these changes may occur due to longer "down" states and state transitions of membrane potentials. The nature of these findings is not completely clear. One important point to consider may be the temperature-related effects of anaesthesia that ultimately lead to increased phosphorylation of tau via a signalling cascade that is sensitive to the body temperature drop by only a few degrees (Planel et al., 2008). It is not clear how the increase in tau phosphorylation may translate into the patterns of neuronal firing and sub-threshold membrane potential dynamics during intracellular recordings in the present study, but it may render tau mice more susceptible to the effects. Thus, the article prompts more experiments on non-anesthetized animals to clarify this. In the present study, intracellular and extracellular recordings were performed in separate experiments. While this design does not undermine the conclusions, it would be insightful to study the unitary, cellular, and network activities during simultaneous recordings.
The study also found that neocortical activity was globally reduced to a greater degree in older animals with higher levels of neurofibrillary tangles; however, the activity was also reduced in neurons without detectable levels of pathological tau. The authors propose that the effects of pathological tau on a fraction of neurons may further amplify and spread throughout the entire cortical network. This would imply that a neuron may receive the adverse effects indirectly from the other affected neurons and in the absence of pathological tau. This mechanism may have broader implications for other neurological diseases associated with misfolding and aggregation of toxic proteins. However, it remains to be determined whether the findings can be explained by soluble tau (elevated at this stage), or even pathological tau that falls below the detection threshold of commonly used techniques, as suggested by the authors and others (Oh et al., 2010). In short, the paper prompts more studies to improve the detection methods routinely used in the field.
Previous studies of the rTg4510 model have also reported that structural and functional changes in layer III frontal cortical pyramidal neurons were not associated with the presence of neurofibrillary tangles, even in mice 8.5- to 9.5-months of age (Rocher et al., 2010; Crimins et al., 2011). Rigorous in vitro studies have also demonstrated that increased excitability and higher action potential firing rates (attributed to depolarized resting membrane potential) were typical for neurons of tau mice, in contrast to the present in vivo findings (Rocher et al., 2010). This discrepancy between in vivo and in vitro results may be due to the inherent differences between preparation and recording techniques (as stated by the authors) or to age-related differences. Further in vivo studies are needed. In APP/PS1 mice, for example, intracellular recordings of hippocampal CA1 neurons at late-stage disease (10 to 14 months of age) reveal elevated firing rates and frequent occurrence of action potential bursts in vivo that are confirmed by recordings in slices (Šišková et al., 2014). In the rTg4510 model it would have been interesting to compare the outcomes of slice recordings reported by Menkes-Caspi et al. with previous studies of the rTg4510 model.
The relationship between tau and another neurotoxic protein, Aβ, has been studied extensively by others in the field. One study has observed that reducing tau levels ameliorates spontaneous epileptiform activity and also the severity of spontaneous and induced seizures in several transgenic mouse lines overexpressing human amyloid precursor protein. Following tau reduction, inhibitory currents recorded in acute hippocampal slices were increased and the balance between excitation and inhibition was restored (Roberson et al., 2011).
More comprehensive studies using powerful experimental approaches, such as included in the current work, will be required to finally dissect out the mechanisms underlying neuronal and brain network abnormalities induced by the interactions of several toxic proteins in individuals with Alzheimer’s disease and other neurological conditions.
References:
Crimins JL, Rocher AB, Peters A, Shultz P, Lewis J, Luebke JI. Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy. Acta Neuropathol. 2011 Nov;122(5):551-64. PubMed.
Oh KJ, Perez SE, Lagalwar S, Vana L, Binder L, Mufson EJ. Staging of Alzheimer's pathology in triple transgenic mice: a light and electron microscopic analysis. Int J Alzheimers Dis. 2010;2010 PubMed.
Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE. Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo. J Neurosci. 2008 Nov 26;28(48):12798-807. PubMed.
Roberson ED, Halabisky B, Yoo JW, Yao J, Chin J, Yan F, Wu T, Hamto P, Devidze N, Yu GQ, Palop JJ, Noebels JL, Mucke L. Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12;31(2):700-11. PubMed.
Rocher AB, Crimins JL, Amatrudo JM, Kinson MS, Todd-Brown MA, Lewis J, Luebke JI. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol. 2010 Jun;223(2):385-93. PubMed.
Šišková Z, Justus D, Kaneko H, Friedrichs D, Henneberg N, Beutel T, Pitsch J, Schoch S, Becker A, von der Kammer H, Remy S. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron. 2014 Dec 3;84(5):1023-33. Epub 2014 Nov 13 PubMed.
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