Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex
Abstract
:1. Introduction
2. Results
2.1. Light Microscopy of Perisomatic Inhibitory Cells
2.1.1. Parvalbumin-Positive Interneurons
2.1.2. CB1 Cannabinoid Receptor-Positive Inhibitory Cells
2.2. Electron Microscopy
2.2.1. Changes Related to Epilepsy
2.2.2. Changes in the Two Perisomatic Basket Cell Axonal Clouds
2.2.3. Differences between Regions Generating and Lacking SPA
2.3. Role of Perisomatic Inhibitory Cells in Synchrony Generation
2.3.1. Role of PV-Positive Cells
2.3.2. Role of CB1R-Positive Cells
3. Discussion
3.1. Changes in the Perisomatic Inhibition Related to Epilepsy
3.2. Cholinergic Input of Pyramidal Cells and Epilepsy
3.3. Perisomatic Inhibitory Interneurons and Synchrony Generation
4. Materials and Methods
4.1. Patients
4.2. Epileptic Patients
4.3. Non-Epileptic Patients
4.4. Tissue Preparation
4.5. Recordings
4.6. Data Analysis
4.7. Histology
4.8. Statistics
4.8.1. Histology
4.8.2. Electrophysiology
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Stage of Epilepsy | Gender | Age | Duration of Epilepsy | Histology/Diagnosis | Resected Cortical Region | Experiment | Seizure Onset Zone | Distance from Tumor | Anatomy of Obtained Tissue |
---|---|---|---|---|---|---|---|---|---|
NoEpi | M | 81 | glioblastoma multiforme grade IV | temporal | EM | close | infiltrated/normal | ||
NoEpi | M | 32 | anaplastic astrocytoma grade III | temporal | pharm | close | infiltrated | ||
NoEpi | F | 63 | lung carcinoma metastasis | occipital | pharm | close | normal | ||
NoEpi | M | 64 | lung adenocarcinoma metastasis | frontal | pharm | close | compressed neocortex | ||
NoEpi | M | 67 | diffuse large B cell lymphoma | frontal | pharm | close | normal | ||
NoEpi | F | 78 | glioblastoma grade IV | temporal | EM, pharm | distant | normal | ||
NoEpi | F | 65 | glioblastoma multiforme | temporal | EM, pharm | close | normal | ||
NoEpi | F | 52 | glioblastoma grade IV | parietal | distant | infiltrated | |||
NoEpi | F | 36 | anaplastic ependymoma grade III | parietal | pharm | distant | normal | ||
NoEpi | F | 55 | glioblastoma multiforme | frontal | pharm | distant | normal | ||
NoEpi | F | 59 | breast carcinoma metastasis | frontal | close | infiltrated | |||
NoEpi | F | 68 | glioblastoma multiforme grade IV | temporal | EM | close | normal | ||
NoEpi | F | 67 | glioblastoma multiforme grade IV | parietal | close | normal | |||
ResEpi | M | 39 | 35 years | hippocampal sclerosis | temporal | EM | no | - | normal |
ResEpi | F | 53 | 40 years | hippocampal sclerosis | temporal | EM | no | - | normal |
ResEpi | M | 35 | 34 years | focal cortical dysplasia + hippocampal sclerosis | temporal | EM | no | - | normal |
ResEpi | M | 32 | 23 years | focal cortical dysplasia IIb with balloon cells | temporal | EM | no | - | normal |
ResEpi | F | 41 | 9 years | hippocampal and cortical gliosis, microglia activation | temporal | EM | no | - | dysgenetic |
ResEpi | F | 34 | 3 years | cortical gliosis | temporal | pharm | yes | - | normal |
ResEpi | M | 37 | 19 years | cortical gliosis, microglia activation | temporal | pharm | no | - | normal |
ResEpi | M | 32 | 19 years | ganglioglioma grade I | temporal | yes | close | normal | |
ResEpi | M | 30 | 6 years | hippocampal sclerosis, reactive astrocytosis, microglia activation | temporal | pharm | no | - | normal |
ResEpi | F | 28 | 27 years | diffuse glioneural tumor grade I | temporal | EM, pharm | no | distant | normal |
ResEpi | F | 48 | 10 months | diffuse astrocytoma grade II | temporal | pharm | yes | close | normal |
ResEpi | M | 45 | 43 years | stroke induced lesion | frontal | pharm | yes | distant | dysgenetic |
NoEpi | ResEpi | |||||
---|---|---|---|---|---|---|
Total | SPA | No SPA | Total | SPA | No SPA | |
Overall synaptic coverage | 1.07 [0.62–1.50] n = 123 cells | 1.07 [0.80–1.46] n = 57 cells | 1.07 [0.55–1.52] n = 66 cells | 1.12 [0.64–1.67] n = 156 cells | 1.03 [0.56–1.51] n = 81 cells | 1.23 [0.69–1.70] n = 75 cells |
PV+ synaptic coverage | 1.07 [0.58–1.52] n = 62 cells | 0.52 [0.36–0.75] n = 26 cells | 0.52 [0.00–0.90] n = 36 cells | 1.18 [0.57–1.70] n = 78 cells | 0.34 [0.00–0.68] n = 42 cells | 0.35 [0.00–0.67] n = 36 cells |
% of PV+ synaptic coverage | 46.75 [0.00–58.41] | 45.74 [0.00–52.86] | 52.48 [0.00–75.41] | 30.18 [0.00–54.44] | 27.24 [0.00–53.68] | 32.72 [0.00–58.29] |
CB1R+ synaptic coverage | 1.04 [0.68–1.46] n = 61 cells | 0.42 [0.00–0.63] n = 31 cells | 0.37 [0.00–0.68] n = 30 cells | 1.05 [0.65–1.62] n = 78 cells | 0.38 [0.00–0.58] n = 39 cells | 0.62 [0.30–0.80] n = 39 cells |
% of CB1R+ synaptic coverage | 42.82 [0.00–57.28] | 48.35 [0.00–59.98] | 34.75 [0.00–51.16] | 44.66 [22.23–62.72] | 44.18 [0.00–63.62] | 47.76 [31.33–58.73] |
Average length of synaptic active zones (µm) | 0.229 [0.201–0.260] n = 325 boutons | 0.225 [0.198–0.255] n = 129 boutons | 0.230 [0.201–0.267] n = 196 boutons | 0.244 [0.211–0.270] n = 333 boutons | 0.249 [0.213–0.274] n = 188 boutons | 0.237 [0.207–0.266] n = 145 boutons |
Average length of synaptic active zones of PV+ terminals | 0.228 [0.200–0.256] n = 60 boutons | 0.231 [0.203–0.253] ** n = 25 boutons | 0.228 [0.196–0.263] n = 35 boutons | 0.255 [0.228–0.275] n = 65 boutons | 0.260 [0.243–0.276] ** n = 36 boutons | 0.244 [0.217–0.275] n = 29 boutons |
Average length of synaptic active zones of PV− terminals | 0.228 [0.194–0.257] n = 77 boutons | 0.234 [0.201–0.258] n = 40 boutons | 0.212 [0.179–0.249] n = 37 boutons | 0.241 [0.212–0.262] n = 129 boutons | 0.240 [0.209–0.259] n = 73 boutons | 0.242 [0.213–0.264] n = 56 boutons |
Average length of synaptic active zones of CB1R+ terminals | 0.229 [0.196–0.264] n = 77 boutons | 0.216 [0.193–0.255] n = 26 boutons | 0.241 [0.198–0.277] n = 51 boutons | 0.226 [0.193–0.282] n = 61 boutons | 0.237 [0.154–0.291] n = 34 boutons | 0.226 [0.195–0.253] n = 27 boutons |
Average length of synaptic active zones of CB1R− terminals | 0.230 [0.208–0.263] n = 109 boutons | 0.219 [0.199–0.245] * n = 36 boutons | 0.241 [0.211–0.276] n = 73 boutons | 0.248 [0.212–0.273] n = 78 boutons | 0.254 [0.233–0.276] * n = 45 boutons | 0.226 [0.190–0.259] n = 33 boutons |
Average number of PV+ synapses/100 µm soma perimeter | 2.19 [0.00–3.51] n = 62 cells | 2.23 [1.36–3.51] ** n = 26 cells | 2.17 [0.00–3.48] n = 36 cells | 0.25 [0.00–2.06] n = 78 cells | 0.23 [0.00–1.90] ** n = 42 cells | 1.00 [0.00–2.14] n = 36 cells |
Average of PV− synapses/100 µm soma perimeter | 2.49 [1.71–4.09] n = 62 cells | 2.87 [2.12–4.41] * n = 26 cells | 2.17 [0.00–2.76] n = 36 cells | 2.13 [0.30–3.81] n = 78 cells | 2.15 [0.24–3.81] * n = 42 cells | 2.09 [1.21–3.56] n = 36 cells |
Average of CB1R+ synapses/100 µm soma perimeter | 2.07 [0.00–2.80] n = 61 cells | 2.21 [0.00–3.04] n = 31 cells | 1.87 [0.00–2.47] n = 30 cells | 2.02 [0.00–3.20] n = 77 cells | 1.87 [0.00–2.63] n = 38 cells | 2.09 [1.41–3.64] n = 39 cells |
Average number of CB1R− synapses/100 µm soma perimeter | 2.62 [2.03–4.23] n = 61 cells | 2.47 [1.89–3.95] n = 31 cells | 3.62 [2.07–4.42] n = 30 cells | 2.65 [1.80–4.53] n = 77 cells | 2.55 [1.31–4.95] n = 38 cells | 2.82 [1.94–4.53] n = 39 cells |
Frequency (Hz) | NoEpi | ResEpi | |||||||
---|---|---|---|---|---|---|---|---|---|
Physiological Solution | Pharmacological Agent | Changes Compared to Physiological Solution (%) | Physiological Solution | Pharmacological Agent | Changes Compared to Physiological Solution (%) | ||||
Carbachol | n = 12 | 1.37 [0.74–1.76] | 1.24 [0.59–1.57] | 80 [72–95] | * | n = 8 | 0.88 [0.67–1.84] | 0.10 [0.02–0.37] * | 9 [3–27] |
AF-DX 116 | n = 3 | 0.98 [0.85–0.99] | 0.97 [0.77–1.02] | 99 [88–102] | n = 4 | 1.28 [0.99–1.56] | 1.33 [1.15–1.48] | 102 [99–107] | |
AF-DX 116 + Carbachol | n = 6 | 0.99 [0.78–1.45] | 0.82 [0.72–1.19] | 78 [75–87] | n = 4 | 1.28 [0.99–1.56] | 0.90 [0.87–1.07] | 83 [71–96] | |
AM-251 | n = 3 | 1.02 [0.61–1.21] | 1.07 [0.63–1.18] | 92 [91–99] | n = 5 | 0.94 [0.81–1.71] | 0.97 [0.93–1.49] | 96 [94–115] | |
AM-251 + Carbachol | n = 5 | 1.40 [1.23–1.51] | 1.47 [1.03–1.50] | 88 [84–97] | n = 5 | 0.94 [0.81–1.71] | 0.83 [0.02–0.94] | 88 [2–93] |
LFPg Amplitude (µV) | NoEpi | ResEpi | |||||||
---|---|---|---|---|---|---|---|---|---|
Physiological Solution | Pharmacological Agent | Changes Compared to Physiological Solution (%) | Physiological Solution | Pharmacological Agent | Changes Compared to Physiological Solution (%) | ||||
Carbachol | n = 12 | 36.30 [25.01–46.44] | 23.42 [20.00–31.01] ** | 68 [63–77] | n = 8 | 66.01 [36.46–106.49] | 18.10 [12.20–31.21] ** | 37 [25–45] | |
AF-DX 116 | n = 3 | 38.67 [27.55–38.75] | 34.88 [25.06–41.60] * | 93 [91–109] | ** | n = 4 | 79.43 [60.50–95.75] | 79.70 [59.51–96.74] * | 99 [99–100] |
AF-DX 116 + Carbachol | n = 6 | 38.75 [38.08–62.72] | 34.28 [28.52–39.61] ** | 92 [75–96] | ** | n = 4 | 79.43 [60.50–95.75] | 63.87 [53.55–76.51] *** | 87 [83–91] |
AM-251 | n = 3 | 35.48 [29.46–41.67] | 29.71 [28.06–41.98] * | 113 [98–113] | * | n = 5 | 55.66 [46.00–89.09] | 63.13 [46.15–88.51] * | 100 [99–100] |
AM-251 + Carbachol | n = 5 | 39.80 [27.18–46.92] | 22.81 [22.34–34.12] ** | 68 [64–95] | * | n = 5 | 55.66 [46.00–89.09] | 22.78 [11.18–33.91] *** | 38 [34–50] |
MUA Amplitude (µV) | NoEpi | ResEpi | |||||||
---|---|---|---|---|---|---|---|---|---|
Physiological Solution | Pharmacological Agent | Changes Compared to Physiological Solution (%) | Physiological Solution | Pharmacological Agent | Changes Compared to Physiological Solution (%) | ||||
Carbachol | n = 12 | 0.67 [0.56–1.10] | 0.67 [0.46–0.85] | 81 [57–107] | n = 8 | 3.12 [1.82–5.36] | 1.21 [0.41–3.03] | 43 [22–85] | |
AF-DX 116 | n = 3 | 0.98 [0.83–1.10] | 0.94 [0.81–1.22] | 97 [97–110] | * | n = 4 | 3.89 [3.73–4.41] | 4.89 [4.20–5.57] | 113 [102–127] |
AF-DX 116 + Carbachol | n = 6 | 1.10 [0.76–1.41] | 0.75 [0.69–0.95] | 88 [80–97] | * | n = 4 | 3.89 [3.73–4.41] | 4.93 [4.21–5.31] | 111 [86–135] |
AM-251 | n = 3 | 0.87 [0.66–1.04] | 1.24 [0.90–1.99] | 124 [114–219] | n = 5 | 4.07 [2.84–5.20] | 3.73 [2.89–4.13] | 92 [88–102] | |
AM-251 + Carbachol | n = 5 | 0.87 [0.73–1.20] | 1.32 [1.27–1.49] | 139 [122–155] | n = 5 | 4.07 [2.84–5.20] | 2.50 [1.50–4.04] | 65 [64–88] |
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Tóth, E.Z.; Szabó, F.G.; Kandrács, Á.; Molnár, N.O.; Nagy, G.; Bagó, A.G.; Erőss, L.; Fabó, D.; Hajnal, B.; Rácz, B.; et al. Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex. Int. J. Mol. Sci. 2022, 23, 202. https://doi.org/10.3390/ijms23010202
Tóth EZ, Szabó FG, Kandrács Á, Molnár NO, Nagy G, Bagó AG, Erőss L, Fabó D, Hajnal B, Rácz B, et al. Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex. International Journal of Molecular Sciences. 2022; 23(1):202. https://doi.org/10.3390/ijms23010202
Chicago/Turabian StyleTóth, Estilla Zsófia, Felicia Gyöngyvér Szabó, Ágnes Kandrács, Noémi Orsolya Molnár, Gábor Nagy, Attila G. Bagó, Loránd Erőss, Dániel Fabó, Boglárka Hajnal, Bence Rácz, and et al. 2022. "Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex" International Journal of Molecular Sciences 23, no. 1: 202. https://doi.org/10.3390/ijms23010202