Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Abstract

Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

“…Furthermore, metformin was able to increase the hippocampal levels of antioxidant enzymes, such as superoxide dismutase levels [ 121 ]. These results give support to the hypothesis that metformin could be a potential preventive drug against cognitive and memory impairment [ 94 , 95 , 121 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ] ( Table 1 ). Similarly, metformin was shown to prevent cognitive damage in the chronic L-methionine model of memory impairment, probably by normalizing oxidative damage [ 124 ].…”

“…Likewise, since the hippocampus is an essential part of the brain for memory and cognition and it is widely affected in AD, the hippocampus’ neuronal activation and synaptic transmission are important for improving these functions. According to Chen and colleagues, metformin improved synapsis, memory, and cognitive deficits with disrupted hippocampal synaptic communication [ 131 ]. This process could be explained through the increased presynaptic glutamate release, which would be responsible for the increased elevated miniature excitatory postsynaptic currents (mEPSC) into CA1 pyramid neurons in hippocampus [ 131 ].…”

“…According to Chen and colleagues, metformin improved synapsis, memory, and cognitive deficits with disrupted hippocampal synaptic communication [ 131 ]. This process could be explained through the increased presynaptic glutamate release, which would be responsible for the increased elevated miniature excitatory postsynaptic currents (mEPSC) into CA1 pyramid neurons in hippocampus [ 131 ]. Likewise, Asadbegi and colleagues demonstrated that metformin treatment was able to improve significantly long-term potentiation in rats after the Aβ-injection.…”

“…Hence, it is accepted that insulin improves emotional function in active and elderly people, as well as Alzheimer’s patients [ 128 ]. Insulin signaling can influence the synaptic plasticity by controlling glutamate receptor expression and trafficking, and insulin receptors are enriched at hippocampal synapses, where they are proposed to control synaptic plasticity by interactions with the glutamatergic system [ 95 , 128 , 129 , 130 , 131 ]. Furthermore, various studies have shown that synaptic markers and/or dendritic spine dysfunction appear before the development of Aβ plaques and NFTs, thus implying that these events are closely linked to cognitive decline in AD [ 95 , 128 , 129 , 130 , 131 , 132 ].…”

“…Insulin signaling can influence the synaptic plasticity by controlling glutamate receptor expression and trafficking, and insulin receptors are enriched at hippocampal synapses, where they are proposed to control synaptic plasticity by interactions with the glutamatergic system [ 95 , 128 , 129 , 130 , 131 ]. Furthermore, various studies have shown that synaptic markers and/or dendritic spine dysfunction appear before the development of Aβ plaques and NFTs, thus implying that these events are closely linked to cognitive decline in AD [ 95 , 128 , 129 , 130 , 131 , 132 ]. In older rhesus monkeys, selective loss of thin spines is closely associated with decreased learning capacity [ 134 , 135 , 136 ].…”