M. Simonato - Academia.edu (original) (raw)
Papers by M. Simonato
Proceedings of the National Academy of Sciences, 2010
Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling ... more Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling mediated by GABA A receptors. In particular, the use-dependent decrease (run-down) of the currents (I GABA ) evoked by the repetitive activation of GABA A receptors is markedly enhanced in hippocampal and cortical neurons of TLE patients. Understanding the role of I GABA run-down in the disease, and its mechanisms, may allow development of medical alternatives to surgical resection, but such mechanistic insights are difficult to pursue in surgical human tissue. Therefore, we have used an animal model (pilocarpine-treated rats) to identify when and where the increase in I GABA run-down occurs in the natural history of epilepsy. We found: (i) that the increased run-down occurs in the hippocampus at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made), and then extends to the neocortex and remains constant in the course of the disease; (ii) that the phenomenon is strictly correlated with the occurrence of spontaneous seizures, because it is not observed in animals that do not become epileptic. Furthermore, initial exploration of the molecular mechanism disclosed a relative increase in α4-, relative to α1-containing GABA A receptors, occurring at the same time when the increased run-down appears, suggesting that alterations in the molecular composition of the GABA receptors may be responsible for the occurrence of the increased run-down. These observations disclose research opportunities in the field of epileptogenesis that may lead to a better understanding of the mechanism whereby a previously normal tissue becomes epileptic. GABA A receptor | pilocarpine rat | Xenopus oocytes
Brain Research, 1999
One goal of neuroscience is to define the molecular and cellular basis for behavior and neurologi... more One goal of neuroscience is to define the molecular and cellular basis for behavior and neurological diseases. A novel approach to this problem is based on the use of viral vectors to transfect specific genes into specific brain cell populations. This review focuses on herpes simplex-based vectors. Major advances have recently been made to improve the characteristics of these vectors, in particular to reduce their toxicity, to modulate the greatness and the time-course of transgene expression, to precisely target specific cell populations, and to transfer multiple genes. Much remains to be done to obtain robust and prolonged transgene expression. However, specific alterations in the behavior and in disease models have already been described following the herpes simplex vector-mediated expression of specific genes within highly localized brain areas. Therefore, this research strategy is likely to provide new clues on the cellular and molecular basis of behavior and of neurological diseases. q
Proceedings of the National Academy of Sciences, 2008
We examined how the endogenous anticonvulsant adenosine might influence ␥-aminobutyric acid type ... more We examined how the endogenous anticonvulsant adenosine might influence ␥-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 M), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA A-current (IGABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I GABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated I GABA run-down in Ϸ40% and Ϸ20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 M) potentiated IGABA run-down but only in Ϸ20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABA A-receptor stability is tonically influenced by A2A but not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2-A3 receptors alter the stability of GABA A receptors, which could offer therapeutic opportunities.
Proceedings of the National Academy of Sciences, 2010
Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling ... more Refractory temporal lobe epilepsy (TLE) is associated with a dysfunction of inhibitory signaling mediated by GABA A receptors. In particular, the use-dependent decrease (run-down) of the currents (I GABA ) evoked by the repetitive activation of GABA A receptors is markedly enhanced in hippocampal and cortical neurons of TLE patients. Understanding the role of I GABA run-down in the disease, and its mechanisms, may allow development of medical alternatives to surgical resection, but such mechanistic insights are difficult to pursue in surgical human tissue. Therefore, we have used an animal model (pilocarpine-treated rats) to identify when and where the increase in I GABA run-down occurs in the natural history of epilepsy. We found: (i) that the increased run-down occurs in the hippocampus at the time of the first spontaneous seizure (i.e., when the diagnosis of epilepsy is made), and then extends to the neocortex and remains constant in the course of the disease; (ii) that the phenomenon is strictly correlated with the occurrence of spontaneous seizures, because it is not observed in animals that do not become epileptic. Furthermore, initial exploration of the molecular mechanism disclosed a relative increase in α4-, relative to α1-containing GABA A receptors, occurring at the same time when the increased run-down appears, suggesting that alterations in the molecular composition of the GABA receptors may be responsible for the occurrence of the increased run-down. These observations disclose research opportunities in the field of epileptogenesis that may lead to a better understanding of the mechanism whereby a previously normal tissue becomes epileptic. GABA A receptor | pilocarpine rat | Xenopus oocytes
Brain Research, 1999
One goal of neuroscience is to define the molecular and cellular basis for behavior and neurologi... more One goal of neuroscience is to define the molecular and cellular basis for behavior and neurological diseases. A novel approach to this problem is based on the use of viral vectors to transfect specific genes into specific brain cell populations. This review focuses on herpes simplex-based vectors. Major advances have recently been made to improve the characteristics of these vectors, in particular to reduce their toxicity, to modulate the greatness and the time-course of transgene expression, to precisely target specific cell populations, and to transfer multiple genes. Much remains to be done to obtain robust and prolonged transgene expression. However, specific alterations in the behavior and in disease models have already been described following the herpes simplex vector-mediated expression of specific genes within highly localized brain areas. Therefore, this research strategy is likely to provide new clues on the cellular and molecular basis of behavior and of neurological diseases. q
Proceedings of the National Academy of Sciences, 2008
We examined how the endogenous anticonvulsant adenosine might influence ␥-aminobutyric acid type ... more We examined how the endogenous anticonvulsant adenosine might influence ␥-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 M), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABA A-current (IGABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced I GABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated I GABA run-down in Ϸ40% and Ϸ20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 M) potentiated IGABA run-down but only in Ϸ20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABA A-receptor stability is tonically influenced by A2A but not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2-A3 receptors alter the stability of GABA A receptors, which could offer therapeutic opportunities.