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.
Highlights
The biguanide metformin (Met) has long been used as a first-line drug for type 2 diabetes mellitus (T2DM) therapy
We first investigated the potential role of Met on glutamatergic transmission by performing whole-cell voltage clamp recordings on CA1 pyramidal neurons
Miniature excitatory postsynaptic currents were recorded, with the presence of bicuculline and tetrodotoxin (TTX, voltage-gated sodium channel blocker) blocking inhibitory neurotransmission and action potential (AP), respectively (Figure 1). miniature excitatory postsynaptic currents (mEPSCs) frequencies were dramatically increased in slices treated with Met at concentrations of 1 μM and 10 μM (F(2,35) = 14.53, p < 0.0001, one-way
Summary
The biguanide metformin (Met) has long been used as a first-line drug for type 2 diabetes mellitus (T2DM) therapy. Met lowers the plasma glucose level through inhibiting hepatic glucose production and enhancing insulin sensitivity [1]. Met inhibits the mitochondrial respiratory chain complex I and activates AMP (adenosine monophosphate)-activated protein kinase complex (AMPK) [2,3]. In a fragile X syndrome (FXS) mouse model, Met treatment ameliorated social deficit, repetitive behavior and abnormal dendritic spine morphology and exaggerated long-term depression (LTD) [7]. Improvements in language and cognitive behaviors were observed in a small sample size of Met-treated FXS patients [8,9,10].
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