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Learning and memory require orchestrated regulation of both structural and functional synaptic plasticity in the hippocampus. While a neuropeptide alpha-melanocyte-stimulating hormone, a-MSH, has been implicated in memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored. In this study, we report that activation of MC4R enhances synaptic plasticity through the regulation of dendritic spine morphology and abundance of AMPA receptors. We show that activation of postsynaptic MC4R increases the number of mature dendritic spines and enhances surface expression of AMPA receptor subunit GluAl, resulting in synaptic accumulation of GluAl-containing AMPA receptors. Moreover, MC4R stimulates surface GluAl trafficking through phosphorylation of GluAl at Ser845 in a Gas-cAMP/PKA-dependent manner. Blockade of protein kinase A (PKA) signaling abolishes the MC4R-mediated enhancement of neurotransmission and hippocampal long-term potentiation. Importantly, in vivo application of MC4R agonists increases LTP in the mouse hippocampal CAI region. These findings reveal that MC4R in the hippocampus plays a critical role in the regulation of structural and functional plasticity. [ABSTRACT FROM AUTHOR]

Compounds that have the ability to both strengthen synaptic function and facilitate neuroprotection are valuable cognitive enhancers that may improve health and quality of life, as well as retard age-related cognitive deterioration. Medicinal plants are an abundant source of potential cognitive enhancers. Here we report that anemoside A3 (AA3) isolated from Pulsatilla chinensis modulates synaptic connectivity in circuits central to memory enhancement. AA3 specifically modulates the function of AMPA-type glutamate receptors (AMPARs) by increasing serine phosphorylation within the GluA1 subunit, which is a modification required for the trafficking of GluA1-containing AMPARs to synapses. Furthermore, AA3 administration activates several synaptic signaling molecules and increases protein expressions of the neurotrophin brain-derived neurotrophic factor and monoamine neurotransmitters in the mouse hippocampus. In addition to acting through AMPARs, AA3 also acts as a non-competitive NMDA receptor (NMDAR) modulator with a neuroprotective capacity against ischemic brain injury and overexcitation in rats. These findings collectively suggest that AA3 possesses a unique ability to modulate the functions of both AMPARs and NMDARs. Concordantly, behavioral studies indicate that AA3 not only facilitates hippocampal long-term potentiation but also enhances spatial reference memory formation in mice. These multifaceted roles suggest that AA3 is an attractive candidate for further development as a cognitive enhancer capable of alleviating memory dysfunctions associated with aging and neurodegenerative diseases.