The hippocampus is a key target for the hormone leptin and leptin regulation of excitatory synaptic transmission at Schaffer-collateral–CA1 synapses during aging are well documented. However, little is known about the age-dependent actions of leptin at the temporoammonic (TA) input to CA1 neurons. Here we show that leptin induces a novel form of N-methyl-D-aspartate receptor–dependent long-term depression (LTD) at adult (12–24 weeks old) TA-CA1 synapses. Leptin-induced LTD requires activation of canonical Janus tyrosine kinase 2- signal transducer and activator of transcription signaling and removal of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors from synapses. Moreover, leptin-induced LTD is occluded by activity-dependent LTD at TA-CA1 synapses. By contrast, leptin has no effect on excitatory synaptic transmission at aged (12–14 months old) TA-CA1 synapses, and low-frequency stimulation also fails to induce LTD at this age. These findings demonstrate clear age-related alterations in the leptin sensitivity of TA-CA1 synapses and provide valuable information on how the leptin system alters with age. As leptin has been linked to Alzheimer's disease, these findings have important implications for understanding of age-related disorders such as Alzheimer's disease.

Background and Purpose: 17β estradiol (E2) rapidly regulates excitatory synaptic transmission at the classical Schaffer collateral (SC) input to hippocampal CA1 neurons. However, the impact of E2 on excitatory synaptic transmission at the distinct temporoammonic (TA) input to CA1 neurons and the oestrogen receptors involved is less clear. Experimental Approach: Extracellular recordings were used to monitor excitatory synaptic transmission in hippocampal slices from juvenile male (P11-24) Sprague Dawley rats. Immunocytochemistry combined with confocal microscopy was used to monitor the surface expression of the AMPA receptor (AMPAR) subunit, GluA1 in hippocampal neurons cultured from neonatal (P0-3) rats. Key Results: Here, we show that E2 induces a novel form of LTP at TA-CA1 synapses, an effect mirrored by the ERα agonist, PPT, and blocked by an ERα antagonist. ERα-induced LTP is NMDA receptor (NMDAR)-dependent and involves a postsynaptic expression mechanism that requires PI 3-kinase signalling and synaptic insertion of GluA2-lacking AMPARs. ERα-induced LTP has overlapping expression mechanisms with classical Hebbian LTP, as HFS-induced LTP occluded PPT-induced LTP and vice versa. In addition, activity-dependent LTP was blocked by the ERα antagonist, suggesting that ERα activation is involved in NMDA-LTP at TA-CA1 synapses. Conclusion and Implications: ERα induces a novel form of LTP at juvenile male hippocampal TA-CA1 synapses. As TA-CA1 synapses are implicated in episodic memory processes and are an early target for neurodegeneration, these findings have important implications for the role of oestrogens in CNS health and neurodegenerative disease.

It is well documented that 17β estradiol (E2) regulates excitatory synaptic transmission at hippocampal Shaffer-collateral (SC)-CA1 synapses, via activation of the classical estrogen receptors (ERα and ERβ). Hippocampal CA1 pyramidal neurons are also innervated by the temporoammonic (TA) pathway, and excitatory TA-CA1 synapses are reported to be regulated by E2. Recent studies suggest a role for the novel G-protein coupled estrogen receptor (GPER1) at SC-CA1 synapses, however, the role of GPER1 in mediating the effects of E2 at juvenile TA-CA1 synapses is unclear. Here we demonstrate that the GPER1 agonist, G1 induces a persistent, concentration-dependent (1–10 nM) increase in excitatory synaptic transmission at TA-CA1 synapses and this effect is blocked by selective GPER1 antagonists. The ability of GPER1 to induce this novel form of chemical long-term potentiation (cLTP) was prevented following blockade of N-methyl-d-aspartate (NMDA) receptors, and it was not accompanied by any change in paired pulse facilitation ratio (PPR). GPER1-induced cLTP involved activation of ERK but was independent of phosphoinositide 3-kinase (PI3K) signalling. Prior treatment with philanthotoxin prevented the effects of G1, indicating that synaptic insertion of GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors underlies GPER1-induced cLTP. Furthermore, activity-dependent LTP occluded G1‐induced cLTP and vice versa, indicating that these processes have overlapping expression mechanisms. Activity‐dependent LTP was blocked by the GPER1 antagonist, G15, suggesting that GPER1 plays a role in NMDA‐dependent LTP at juvenile TA‐CA1 synapses. These findings add a new dimension to our understanding of GPER1 in modulating neuronal plasticity with relevance to age-related neurodegenerative conditions.