Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition
Background: N-methyl-D-aspartate type glutamate receptors (NMDARs) are fundamental to neuronal physiology and pathophysiology. The prefrontal cortex (PFC), a key region for cognitive function, is heavily implicated in neuropsychiatric disorders, positioning the modulation of its glutamatergic neurot...
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2024-12-01
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| author | Zsolt Tamás Papp Polett Ribiczey Erzsébet Kató Zsuzsanna E. Tóth Zoltán V. Varga Zoltán Giricz Adrienn Hanuska Mahmoud Al-Khrasani Ákos Zsembery Tibor Zelles Laszlo G. Harsing László Köles |
| author_facet | Zsolt Tamás Papp Polett Ribiczey Erzsébet Kató Zsuzsanna E. Tóth Zoltán V. Varga Zoltán Giricz Adrienn Hanuska Mahmoud Al-Khrasani Ákos Zsembery Tibor Zelles Laszlo G. Harsing László Köles |
| author_sort | Zsolt Tamás Papp |
| collection | DOAJ |
| description | Background: N-methyl-D-aspartate type glutamate receptors (NMDARs) are fundamental to neuronal physiology and pathophysiology. The prefrontal cortex (PFC), a key region for cognitive function, is heavily implicated in neuropsychiatric disorders, positioning the modulation of its glutamatergic neurotransmission as a promising therapeutic target. Our recently published findings indicate that AT<sub>1</sub> receptor activation enhances NMDAR activity in layer V pyramidal neurons of the rat PFC. At the same time, it suggests that alternative angiotensin pathways, presumably involving AT<sub>4</sub> receptors (AT4Rs), might exert inhibitory effects. Angiotensin IV (Ang IV) and its analogs have demonstrated cognitive benefits in animal models of learning and memory deficits. Methods: Immunohistochemistry and whole-cell patch-clamp techniques were used to map the cell-type-specific localization of AT4R, identical to insulin-regulated aminopeptidase (IRAP), and to investigate the modulatory effects of Ang IV on NMDAR function in layer V pyramidal cells of the rat PFC. Results: AT4R/IRAP expression was detected in pyramidal cells and GABAergic interneurons, but not in microglia or astrocytes, in layer V of the PFC in 9–12-day-old and 6-month-old rats. NMDA (30 μM) induced stable inward cation currents, significantly inhibited by Ang IV (1 nM–1 µM) in a subset of pyramidal neurons. This inhibition was reproduced by the IRAP inhibitor LVVYP-H7 (10–100 nM). Synaptic isolation of pyramidal neurons did not affect the Ang IV-mediated inhibition of NMDA currents. Conclusions: Ang IV/IRAP-mediated inhibition of NMDA currents in layer V pyramidal neurons of the PFC may represent a way of regulating cognitive functions and thus a potential pharmacological target for cognitive impairments and related neuropsychiatric disorders. |
| format | Article |
| id | doaj-art-6e3c8414ec3040adba905147364c76b8 |
| institution | Kabale University |
| issn | 2227-9059 |
| language | English |
| publishDate | 2024-12-01 |
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| series | Biomedicines |
| spelling | doaj-art-6e3c8414ec3040adba905147364c76b82025-01-24T13:23:55ZengMDPI AGBiomedicines2227-90592024-12-011317110.3390/biomedicines13010071Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA InhibitionZsolt Tamás Papp0Polett Ribiczey1Erzsébet Kató2Zsuzsanna E. Tóth3Zoltán V. Varga4Zoltán Giricz5Adrienn Hanuska6Mahmoud Al-Khrasani7Ákos Zsembery8Tibor Zelles9Laszlo G. Harsing10László Köles11Department of Oral Biology, Semmelweis University, H-1089 Budapest, HungaryDepartment of Oral Biology, Semmelweis University, H-1089 Budapest, HungaryDepartment of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, HungaryLaboratory of Neuroendocrinology and In Situ Hybridization, Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, HungaryDepartment of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, HungaryDepartment of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, HungaryDepartment of Oral Biology, Semmelweis University, H-1089 Budapest, HungaryDepartment of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, HungaryDepartment of Oral Biology, Semmelweis University, H-1089 Budapest, HungaryDepartment of Oral Biology, Semmelweis University, H-1089 Budapest, HungaryDepartment of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, HungaryDepartment of Oral Biology, Semmelweis University, H-1089 Budapest, HungaryBackground: N-methyl-D-aspartate type glutamate receptors (NMDARs) are fundamental to neuronal physiology and pathophysiology. The prefrontal cortex (PFC), a key region for cognitive function, is heavily implicated in neuropsychiatric disorders, positioning the modulation of its glutamatergic neurotransmission as a promising therapeutic target. Our recently published findings indicate that AT<sub>1</sub> receptor activation enhances NMDAR activity in layer V pyramidal neurons of the rat PFC. At the same time, it suggests that alternative angiotensin pathways, presumably involving AT<sub>4</sub> receptors (AT4Rs), might exert inhibitory effects. Angiotensin IV (Ang IV) and its analogs have demonstrated cognitive benefits in animal models of learning and memory deficits. Methods: Immunohistochemistry and whole-cell patch-clamp techniques were used to map the cell-type-specific localization of AT4R, identical to insulin-regulated aminopeptidase (IRAP), and to investigate the modulatory effects of Ang IV on NMDAR function in layer V pyramidal cells of the rat PFC. Results: AT4R/IRAP expression was detected in pyramidal cells and GABAergic interneurons, but not in microglia or astrocytes, in layer V of the PFC in 9–12-day-old and 6-month-old rats. NMDA (30 μM) induced stable inward cation currents, significantly inhibited by Ang IV (1 nM–1 µM) in a subset of pyramidal neurons. This inhibition was reproduced by the IRAP inhibitor LVVYP-H7 (10–100 nM). Synaptic isolation of pyramidal neurons did not affect the Ang IV-mediated inhibition of NMDA currents. Conclusions: Ang IV/IRAP-mediated inhibition of NMDA currents in layer V pyramidal neurons of the PFC may represent a way of regulating cognitive functions and thus a potential pharmacological target for cognitive impairments and related neuropsychiatric disorders.https://www.mdpi.com/2227-9059/13/1/71N-methyl-D-aspartate receptorAT<sub>4</sub> angiotensin receptorinsulin-regulated aminopeptidaseprefrontal cortexrenin–angiotensin systemneuromodulation |
| spellingShingle | Zsolt Tamás Papp Polett Ribiczey Erzsébet Kató Zsuzsanna E. Tóth Zoltán V. Varga Zoltán Giricz Adrienn Hanuska Mahmoud Al-Khrasani Ákos Zsembery Tibor Zelles Laszlo G. Harsing László Köles Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition Biomedicines N-methyl-D-aspartate receptor AT<sub>4</sub> angiotensin receptor insulin-regulated aminopeptidase prefrontal cortex renin–angiotensin system neuromodulation |
| title | Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition |
| title_full | Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition |
| title_fullStr | Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition |
| title_full_unstemmed | Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition |
| title_short | Angiotensin IV Receptors in the Rat Prefrontal Cortex: Neuronal Expression and NMDA Inhibition |
| title_sort | angiotensin iv receptors in the rat prefrontal cortex neuronal expression and nmda inhibition |
| topic | N-methyl-D-aspartate receptor AT<sub>4</sub> angiotensin receptor insulin-regulated aminopeptidase prefrontal cortex renin–angiotensin system neuromodulation |
| url | https://www.mdpi.com/2227-9059/13/1/71 |
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