Electrophysiology and Morphology of Human Cortical Supragranular Pyramidal Cells in a Wide Age Range
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eLife Assessment
Barzó et al. assessed the electrophysiological and anatomical properties of a large number of layer 2/3 pyramidal neurons in brain slices of human neocortex across a wide range of ages, from infancy to elderly individuals, using whole-cell patch clamp recordings and anatomical reconstructions. This large data set represents a valuable contribution to our understanding of how these properties change across the human lifespan, and although the results presented are convincing, analyzing the data by absolute age rather than age ranges as well as clarifying the methods used and some of the statistical approaches applied would strengthen the conclusions. The analysis of spine density requires additional biological replicates to support the conclusions stated. These data strengthen our understanding of how these properties change with age and will contribute to building more realistic models of human cortical function.
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Abstract
The basic excitatory neurons of the cerebral cortex, the pyramidal cells, are the most important signal integrators for the local circuit. They have quite characteristic morphological and electrophysiological properties that are known to be largely constant with age in the young and adult cortex. However, the brain undergoes several dynamic changes throughout life, such as in the phases of early development and cognitive decline in the aging brain. We set out to search for intrinsic cellular changes in supragranular pyramidal cells across a broad age range: from birth to 85 years of age and we found differences in several biophysical properties between defined age groups. During the first year of life, subthreshold and suprathreshold electrophysiological properties changed in a way that shows that pyramidal cells become less excitable with maturation, but also become temporarily more precise. According to our findings, the morphological features of the three-dimensional reconstructions from different life stages showed consistent morphological properties and systematic dendritic spine analysis of an infantile and an old pyramidal cell showed clear significant differences in the distribution of spine shapes. Overall, the changes that occur during development and aging may have lasting effects on the properties of pyramidal cells in the cerebral cortex. Understanding these changes is important to unravel the complex mechanisms underlying brain development, cognition and age-related neurodegenerative diseases.
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eLife Assessment
Barzó et al. assessed the electrophysiological and anatomical properties of a large number of layer 2/3 pyramidal neurons in brain slices of human neocortex across a wide range of ages, from infancy to elderly individuals, using whole-cell patch clamp recordings and anatomical reconstructions. This large data set represents a valuable contribution to our understanding of how these properties change across the human lifespan, and although the results presented are convincing, analyzing the data by absolute age rather than age ranges as well as clarifying the methods used and some of the statistical approaches applied would strengthen the conclusions. The analysis of spine density requires additional biological replicates to support the conclusions stated. These data strengthen our understanding of how these properties …
eLife Assessment
Barzó et al. assessed the electrophysiological and anatomical properties of a large number of layer 2/3 pyramidal neurons in brain slices of human neocortex across a wide range of ages, from infancy to elderly individuals, using whole-cell patch clamp recordings and anatomical reconstructions. This large data set represents a valuable contribution to our understanding of how these properties change across the human lifespan, and although the results presented are convincing, analyzing the data by absolute age rather than age ranges as well as clarifying the methods used and some of the statistical approaches applied would strengthen the conclusions. The analysis of spine density requires additional biological replicates to support the conclusions stated. These data strengthen our understanding of how these properties change with age and will contribute to building more realistic models of human cortical function.
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Reviewer #1 (Public review):
Summary:
The manuscript co-authored by Pál Barzó et al is very clear and very well written, demonstrating the electrophysiological and morphological properties of human cortical layer 2/3 pyramidal cells across a wide age range, from age 1 month to 85 years using whole-cell patch clamp. To my knowledge, this is the first study that looks at the cross-age differences in biophysical and morphological properties of human cortical pyramidal cells. The community will also appreciate the significant effort involved in recording data from 485 cells, given the challenges associated with collecting data from human tissue. Understanding the electrophysiological properties of individual cells, which are essential for brain function, is crucial for comprehending human cortical circuits. I think this research enhances …
Reviewer #1 (Public review):
Summary:
The manuscript co-authored by Pál Barzó et al is very clear and very well written, demonstrating the electrophysiological and morphological properties of human cortical layer 2/3 pyramidal cells across a wide age range, from age 1 month to 85 years using whole-cell patch clamp. To my knowledge, this is the first study that looks at the cross-age differences in biophysical and morphological properties of human cortical pyramidal cells. The community will also appreciate the significant effort involved in recording data from 485 cells, given the challenges associated with collecting data from human tissue. Understanding the electrophysiological properties of individual cells, which are essential for brain function, is crucial for comprehending human cortical circuits. I think this research enhances our knowledge of how biophysical properties change over time in the human cortex. I also think that by building models of human single cells at different ages using these data, we can develop more accurate representations of brain function. This, in turn, provides valuable insights into human cortical circuits and function and helps in predicting changes in biophysical properties in both health and disease.
Strengths:
The strength of this work lies in demonstrating how the electrophysiological and morphological features of human cortical layer 2/3 pyramidal cells change with age, offering crucial insights into brain function throughout life.
Weaknesses:
One potential weakness of the paper is that the methodology could be clearer, especially in how different cells were used for various electrophysiological measurements and the conditions under which the recordings were made. Clarifying these points would improve the study's rigor and make the results easier to interpret.
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Reviewer #2 (Public review):
Summary:
In this study, Barzo and colleagues aim to establish an appraisal for the development of basal electrophysiology of human layer 2/3 pyramidal cells across life and compare their morphological features at the same ages.
Strengths:
The authors have generated recordings from an impressive array of patient samples, allowing them to directly compare the same electrophysiological features as a function of age and other biological features. These data are extremely robust and well organised.
Weaknesses:
The use of spine density and shape characteristics is performed from an extremely limited sample (2 individuals). How reflective these data are of the population is not possible to interpret. Furthermore, these data assume that spines fall into discrete types - which is an increasingly controversial …
Reviewer #2 (Public review):
Summary:
In this study, Barzo and colleagues aim to establish an appraisal for the development of basal electrophysiology of human layer 2/3 pyramidal cells across life and compare their morphological features at the same ages.
Strengths:
The authors have generated recordings from an impressive array of patient samples, allowing them to directly compare the same electrophysiological features as a function of age and other biological features. These data are extremely robust and well organised.
Weaknesses:
The use of spine density and shape characteristics is performed from an extremely limited sample (2 individuals). How reflective these data are of the population is not possible to interpret. Furthermore, these data assume that spines fall into discrete types - which is an increasingly controversial assumption.
Many data are shown according to somewhat arbitrary age ranges. It would have been more informative to plot by absolute age, and then perform more rigourous statistics to test age-dependent effects.
Overall, the authors achieve their aims by assessing the physiological and morphological properties of human L2/3 pyramidal neurons across life. Their findings have extremely important ramifications for our understanding of human life and implications for how different neuronal properties may influence neurological conditions.
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Reviewer #3 (Public review):
Summary:
To understand the specificity of age-dependent changes in the human neocortex, this paper investigated the electrophysiological and morphological characteristics of pyramidal cells in a wide age range from infants to the elderly.
The results show that some electrophysiological characteristics change with age, particularly in early childhood. In contrast, the larger morphological structures, such as the spatial extent and branching frequency of dendrites, remained largely stable from infancy to old age. On the other hand, the shape of dendritic spines is considered immature in infancy, i.e., the proportion of mushroom-shaped spines increases with age.
Strengths:
Whole-cell recordings and intracellular staining of pyramidal cells in defined areas of the human neocortex allowed the authors to compare …
Reviewer #3 (Public review):
Summary:
To understand the specificity of age-dependent changes in the human neocortex, this paper investigated the electrophysiological and morphological characteristics of pyramidal cells in a wide age range from infants to the elderly.
The results show that some electrophysiological characteristics change with age, particularly in early childhood. In contrast, the larger morphological structures, such as the spatial extent and branching frequency of dendrites, remained largely stable from infancy to old age. On the other hand, the shape of dendritic spines is considered immature in infancy, i.e., the proportion of mushroom-shaped spines increases with age.
Strengths:
Whole-cell recordings and intracellular staining of pyramidal cells in defined areas of the human neocortex allowed the authors to compare quantitative parameters of electrophysiological and morphological properties between finely divided age groups.
They succeeded in finding symmetrical changes specific to both infants and the elderly, and asymmetrical changes specific to either infants or the elderly. The similarity of pyramidal cell characteristics between areas is unexpected.
Weaknesses:
Human L2/3 pyramidal cells are thought to be heterogeneous, as L2/3 has expanded to a high degree during the evolution from rodents to humans. However, the diversity (subtyping) is not revealed in this paper.
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