Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study"
The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the ‘tonic’ release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2012-11-01
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| Series: | Frontiers in Neural Circuits |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncir.2012.00094/full |
| _version_ | 1818586836281327616 |
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| author | Giulia ePuia Francesca eGULLO Elena eDossi Marzia eLecchi Enzo eWanke |
| author_facet | Giulia ePuia Francesca eGULLO Elena eDossi Marzia eLecchi Enzo eWanke |
| author_sort | Giulia ePuia |
| collection | DOAJ |
| description | The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the ‘tonic’ release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines (BDZs), enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in-vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissociated neocortical neuron networks grown in long-term culture. We used a multi-electrode array (MEA) recording technique and a novel analysis that was able to both identify the action potentials of engaged excitatory and inhibitory neurons and to detect drug-induced network up-states (burst). We found that the NSs tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) applied at low nM concentrations, produced different modulatory effects on the two neuronal clusters. Conversely, at high concentrations (1 µM), both NSs, decreased excitatory and inhibitory neuron cluster excitability; however, even several hours after washout, the excitability of inhibitory neurons continued to be depressed, leading to a network long term depression (LTD). The BDZs clonazepam (CLZ) and midazolam (MDZ) also decreased the network excitability, but only MDZ caused LTD of inhibitory neuron cluster. To investigate the origin of the LTD after MDZ application, we tested finasteride (FIN), an inhibitor of endogenous NSs synthesis. FIN did not prevent the LTD induced by MDZ, but surprisingly induced it after application of CLZ. The significance and possible mechanisms underlying these LTD effects of NSs and BDZs are discussed. Taken together, our results not only demonstrate that ex-vivo networks show a sensitivity to NSs and BDZs comparable to that expressed in vivo, but also provide a new global in-vitro description that can help in understanding their activity in more complex systems. |
| first_indexed | 2024-12-16T08:59:17Z |
| format | Article |
| id | doaj.art-60517124bfb44d1b884360a8757877bb |
| institution | Directory Open Access Journal |
| issn | 1662-5110 |
| language | English |
| last_indexed | 2024-12-16T08:59:17Z |
| publishDate | 2012-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neural Circuits |
| spelling | doaj.art-60517124bfb44d1b884360a8757877bb2022-12-21T22:37:13ZengFrontiers Media S.A.Frontiers in Neural Circuits1662-51102012-11-01610.3389/fncir.2012.0009430292Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study"Giulia ePuia0Francesca eGULLO1Elena eDossi2Marzia eLecchi3Enzo eWanke4University of Modena and Reggio EmiliaUniversity MilanoBicoccaUniversity MilanoBicoccaUniversity MilanoBicoccaUniversity MilanoBicoccaThe balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the ‘tonic’ release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines (BDZs), enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in-vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissociated neocortical neuron networks grown in long-term culture. We used a multi-electrode array (MEA) recording technique and a novel analysis that was able to both identify the action potentials of engaged excitatory and inhibitory neurons and to detect drug-induced network up-states (burst). We found that the NSs tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) applied at low nM concentrations, produced different modulatory effects on the two neuronal clusters. Conversely, at high concentrations (1 µM), both NSs, decreased excitatory and inhibitory neuron cluster excitability; however, even several hours after washout, the excitability of inhibitory neurons continued to be depressed, leading to a network long term depression (LTD). The BDZs clonazepam (CLZ) and midazolam (MDZ) also decreased the network excitability, but only MDZ caused LTD of inhibitory neuron cluster. To investigate the origin of the LTD after MDZ application, we tested finasteride (FIN), an inhibitor of endogenous NSs synthesis. FIN did not prevent the LTD induced by MDZ, but surprisingly induced it after application of CLZ. The significance and possible mechanisms underlying these LTD effects of NSs and BDZs are discussed. Taken together, our results not only demonstrate that ex-vivo networks show a sensitivity to NSs and BDZs comparable to that expressed in vivo, but also provide a new global in-vitro description that can help in understanding their activity in more complex systems.http://journal.frontiersin.org/Journal/10.3389/fncir.2012.00094/fullBenzodiazepinesmodulatorsLong-term depressionmultielectrode arrayNeurosteroidsSynaptic connectivity |
| spellingShingle | Giulia ePuia Francesca eGULLO Elena eDossi Marzia eLecchi Enzo eWanke Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study" Frontiers in Neural Circuits Benzodiazepines modulators Long-term depression multielectrode array Neurosteroids Synaptic connectivity |
| title | Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study" |
| title_full | Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study" |
| title_fullStr | Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study" |
| title_full_unstemmed | Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study" |
| title_short | Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array (MEA) recording study" |
| title_sort | novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability a multi electrode array mea recording study quot |
| topic | Benzodiazepines modulators Long-term depression multielectrode array Neurosteroids Synaptic connectivity |
| url | http://journal.frontiersin.org/Journal/10.3389/fncir.2012.00094/full |
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