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BDNF‐Induced Changes in Synaptic Function within the Paraventricular Nucleus of the Hypothalamus (PVN) Increase Blood Pressure
Author(s) -
Thorsdottir Daniella,
Einwag Zachary,
Erdos Benedek
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03675
Subject(s) - endocrinology , medicine , gabaa receptor , rostral ventrolateral medulla , chemistry , inhibitory postsynaptic potential , muscimol , excitatory postsynaptic potential , hypothalamus , blood pressure , receptor , biology , heart rate
Activation of PVN neurons projecting to the rostral ventrolateral medulla and spinal cord increases sympathetic activity and blood pressure (BP). Elevated expression of BDNF in the PVN is known to increase BP and heart rate (HR) and it is a key mechanism mediating stress‐induced cardiovascular responses. However, the underlying mechanisms are not fully understood. BDNF is a neurotrophic factor known to enhance excitatory activity and reduce inhibitory activity broadly in the central nervous system. Further, changes in the excitatory/inhibitory balance in the PVN have been demonstrated to elevate BP and sympathetic activity chronically in various hypertensive models. Here, we tested the hypothesis that increased BDNF expression in the PVN elevates BP in part by increasing the expression of excitatory signaling components and decreasing the expression of inhibitory signaling components in the PVN. Sprague Dawley (SD) rats received bilateral PVN injections of AAV2 viral vectors expressing GFP or myc‐conjugated BDNF (BDNFmyc). Three weeks later, the animals were deeply anesthetized and perfused with PBS and 4% paraformaldehyde. PVN expression of NMDAR1, GABAA‐alpha1, GAD67, KCC2 and synapsin 1a/b were assessed using immunofluorescence, confocal microscopy and image analysis. In a second group of AAV2‐GFP or BDNFmyc‐treated SD rats, BP and HR responses to PVN injections of AP5 (10 mM), an NMDA receptor antagonist, NMDA (100 µM), gabazine (2 mM), a GABAA antagonist, and muscimol (10 mM), a GABAA agonist, were recorded under alpha chloralose‐urethane anesthesia. Our results showed that NMDAR1 protein expression in the PVN was significantly elevated in the BDNF compared to the GFP group (p<0.001). Conversely, GABAA‐alpha1 protein expression in the PVN was significantly higher in the GFP compared to the BDNF group (p<0.01), while KCC2 protein expression was significantly elevated in the BDNF compared to the GFP group (p<0.001). In contrast, GAD67 and synapsin 1a/b expression was unaffected by BDNF treatment. NMDA inhibition led to peak average decreases in BP and HR of ‐17±5 mmHg and ‐61±18 BPM in the BDNF group, compared with ‐2±7 mmHg (p<0.05) and ‐6±1 BPM (p<0.05) in the GFP group. NMDA activation led to peak average increases in BP and decreases in HR of 5±1 mmHg and ‐94±23 BPM in the BDNF group, compared with 8±2 mmHg (n=0.31, n.s.) and ‐40±13 BPM (p<0.05) in the GFP group. GABAA inhibition led to peak average increases in BP and HR of 34±7 mmHg and 97±26 BPM in the BDNF group, compared with 70±12 mmHg (p<0.05) and 155±22 BPM (p=0.12, n.s.) in the GFP group. GABAA activation led to peak average decreases in BP and HR of ‐15±2 mmHg and ‐27±8 BPM in the BDNF group, compared with ‐26±5 mmHg (p<0.05) and ‐48±9 BPM (p<0.05) in the GFP group. In summary, BDNF enhances NMDA receptor‐mediated excitatory synaptic transmission and diminishes GABAA‐mediated inhibitory synaptic transmission in the PVN to elevate BP.