Agmatine decreases long-term potentiation via α2-adrenergic receptor and imidazoline type 1 receptor in the hippocampus

Abstract

Agmatine, a decarboxylation product of L-arginine, has been proposed as a novel neurotransmitter/neuromodulator with diverse neuroprotective and antidepressant-like effects. Although its therapeutic potential has been explored, the precise mechanisms by which agmatine modulates synaptic transmission and plasticity in the hippocampus remain unclear. In this study, we investigated the effects of agmatine on the induction and maintenance of long-term potentiation (LTP) in the CA1 region of mouse hippocampal slices, its ability to counteract amyloid-β (Aβ1-42)-induced LTP impairment, and the receptor systems involved. Bath application of agmatine significantly suppressed the maintenance phase of LTP. Notably, agmatine reversed Aβ-induced deficits in LTP, suggesting a protective effect against synaptic dysfunction. Pharmacological experiments demonstrated that these effects were mediated via α2-adrenergic and imidazoline type I receptors. Paired-pulse facilitation and input-output analyses revealed that agmatine did not alter presynaptic release probability but selectively modulated postsynaptic transmission, particularly under AMPA receptor blockade, indicating a potential regulation of NMDA receptor-mediated signaling. Together, these findings suggest that agmatine modulates hippocampal synaptic plasticity through receptor-specific, postsynaptic mechanisms, and highlight its potential as a therapeutic agent against synaptic impairments in neurodegenerative diseases.

Keywords: Agmatine; Amyloid beta-peptides; Imidazoline receptors (I1 subtype); Long-term potentiation; Receptors; Synaptic plasticity; adrenergic; alpha-2.

Fig. 1. Agmatine concentration-dependent effects on basal synaptic transmission.

(A) After 20 min stable response, agmatine was applied in aCSF solution and perfused during time indicated by bar. Filled circle indicates control group. Open circle indicates 400 µM agmatine group, filled triangle means 500 µM agmatine group. (B) Panel B shows the percent change in fEPSP slope measured at 78–80 min relative to baseline (average of the 20-min pre-drug period). Values in parentheses indicate the number of animals and slices tested in each group. Data are presented as mean ± SEM. *p < 0.05, compared with control group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. aCSF, artificial cerebrospinal fluid; agm, agmatine; fEPSP, field excitatory postsynaptic potential.

Fig. 2. Agmatine modulates long-term potentiation induction in a concentration-dependent manner.

(A) Agmatine was applied in aCSF at the beginning of the recording, which lasted for 180 min after four theta burst stimulation (4TBS). Field excitatory postsynaptic potentials (fEPSPs) were monitored for 180 min following 4TBS. (B) Panel B shows percent changes in fEPSP slope measured at 178–180 min relative to the baseline (average slope during the 20-min pre-4TBS period). Insets show representative traces recorded before (a) and 180 min after (b) 4TBS. (C) Agmatine was applied only during the 4TBS period and subsequently washed out. (D) Panel D shows percent changes in fEPSP slope measured at 58–60 min relative to baseline. In (A) and (B) panels, filled circles indicate the control group, open circles the 50 µM agmatine group, filled triangles the 100 µM agmatine group, and open triangles the 400 µM agmatine group. Data are presented as mean ± SEM. *p < 0.05, **p < 0.01 compared to control group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. aCSF, artificial cerebrospinal fluid.

Fig. 3. Agmatine suppresses LTP maintenance in a dose-dependent manner.

(A) Agmatine was applied in artificial cerebrospinal fluid (aCSF) following four theta burst stimulation (4TBS) and perfused during the period indicated by the horizontal bar. Field excitatory postsynaptic potentials (fEPSPs) were recorded throughout the experiment. Filled circle, open circle, filled triangle, open triangle indicate control group, 50 µM agmatine group, 100 µM agmatine group, 400 µM agmatine group, respectively. (B) Panel B shows percent changes in fEPSP slope measured at 178–180 min after 4TBS, relative to the baseline (average of the 20-min pre-4TBS period). Data are expressed as mean ± SEM. *p < 0.05 compared to control group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. LTP, long-term potentiation.

Fig. 4. Agmatine restores LTP impairment induced by A

β. (A) Aβ1–42 (400 nM) was applied in artificial cerebrospinal fluid (aCSF) from the beginning of the recording. Field excitatory postsynaptic potentials (fEPSPs) were recorded for 180 min following four theta burst stimulation (4TBS). Agmatine (50 µM) was perfused in aCSF for at least 10 min prior to Aβ1–42 application. Filled circle, open circle, and open triangle represent the control group, 400 nM Aβ1-42 group, and 400 nM Aβ1–42 + 50 uM agmatine group respectively. (B) Panel B shows percent changes in fEPSP slope measured at 178–180 min relative to the baseline (average of the 20-min pre-4TBS period). Insets show representative traces recorded before (a) and 180 min after (b) 4TBS. Data are expressed as mean ± SEM. *p < 0.05 compared to Aβ-treated group, analyzed by one-way ANOVA followed by Tukey’s post-hoc test. LTP, long-term potentiation; Aβ, amyloid beta.

Fig. 5. Agmatine exerts its effects

via α1-adrenergic receptors and/or imidazoline type 1 receptors. Bu224 (10 µM), idazoxan (10 µM), efaroxan (10 µM), or prazosin (1 µM) was applied in artificial cerebrospinal fluid (aCSF) at least 10 min prior to the application of agmatine (100 µM). Field excitatory postsynaptic potentials (fEPSPs) were recorded for 180 min following four theta burst stimulation (4TBS). (A, C, E, G) show time-course changes in fEPSP slope under each pharmacological condition. Filled circles represent the control group, open circles the 100 µM agmatine group, and open triangles the group co-treated with agmatine and the respective antagonist (Bu224 in A, idazoxan in C, efaroxan in E, and prazosin in G). (B, D, F, H) show the percent changes in fEPSP slope measured at 178–180 min relative to baseline (average of the 20-min pre-4TBS period). Data are expressed as mean ± SEM. *p < 0.05, **p < 0.01, n.s. = not significant; statistical comparisons were performed using one-way ANOVA followed by Tukey’s post- hoc test.

Fig. 6. Effects of agmatine on presynaptic function and postsynaptic synaptic transmission.

Paired-pulse facilitation (PPF) and input–output (I–O) analyses were conducted to evaluate presynaptic and postsynaptic effects of agmatine (100 µM). (A) Filled and open circles represent PPF responses before and after agmatine treatment, respectively, across inter-stimulus intervals of 25, 50, 100, 200, 400, 1,000, and 2,000 ms. (C) Filled and open circles indicate I–O curves obtained before and after agmatine treatment, respectively. (E) Filled and open circles represent responses in the presence of AP5 alone and AP5 + agmatine, respectively. (G) Filled and open circles indicate responses in the presence of CNQX alone and CNQX + agmatine, respectively. (B, D, F, H) Corresponding bar graphs show the area under the curve (AUC) values calculated from the respective I–O or PPF curves. AUC values were used for statistical comparison of synaptic response efficiency between conditions. Data are presented as mean ± SEM. *p < 0.05 was considered statistically significant. ISI, inter-stimulus interval; FV amp, fiber volley amplitude; fEPSP, field excitatory postsynaptic potential.