Metformin is a first-line drug for treating type 2 diabetes mellitus (T2DM) and one of the most commonly prescribed drugs in the world. Besides its hypoglycemic effects, metformin also can improve cognitive or mood functions in some T2DM patients; moreover, it has been reported that metformin exerts beneficial effects on many neurological disorders, including major depressive disorder (MDD), Alzheimer’s disease (AD) and Fragile X syndrome (FXS); however, the mechanism underlying metformin in the brain is not fully understood. Neurotransmission between neurons is fundamental for brain functions, and its defects have been implicated in many neurological disorders. Recent studies suggest that metformin appears not only to regulate synaptic transmission or plasticity in pathological conditions but also to regulate the balance of excitation and inhibition (E/I balance) in neural networks. In this review, we focused on and reviewed the roles of metformin in brain functions and related neurological disorders, which would give us a deeper understanding of the actions of metformin in the brain.

Parkinson’s disease (PD) is a neurodegenerative disorder closely related to immunity. An important aspect of the pathogenesis of PD is the interaction between α-synuclein and a series of immune cells. Studies have shown that accumulation of α-synuclein can induce an autoimmune response that accelerates the progression of PD. This study discusses the mechanisms underlying the interaction between α-synuclein and the immune system. During the development of PD, abnormally accumulated α-synuclein becomes an autoimmune antigen that binds to Toll-like receptors (TLRs) that activate microglia, which differentiate into the microglia type 1 (M1) subtype. The microglia activate intracellular inflammatory pathways, induce the release of proinflammatory cytokines, and promote the differentiation of cluster of differentiation 4 + (CD4 +) T cells into proinflammatory T helper type 1 (Th1) and T helper type 17 (Th17) subtypes. Given the important role of α-synuclein in the immune system of the patients with PD, identifying potential targets of immunotherapy related to α-synuclein is critical for slowing disease progression. An enhanced understanding of immune-associated mechanisms in PD can guide the development of associated therapeutic strategies in the future.

Metformin, a first-line drug for type 2 diabetes mellitus (T2DM), has been found to reduce depressive symptoms in patients with comorbid depression and other diseases. However, it is largely unclear how metformin ameliorates depressive-like behaviors. Here, we used lipopolysaccharide (LPS) to induce depressive-like behaviors in mice and found that LPS-treated mice exhibited increased immobility in the forced swimming test (FST) and tail suspension test (TST), as well as increased glutamatergic transmission. Furthermore, metformin administration in the LPS-treated mice ameliorated depressive-like behaviors and elevated glutamatergic transmission. Our results suggest that metformin has antidepressant effects and can correct abnormal glutamatergic transmission, providing an insight into the underlying mechanism by which metformin acts against depression.

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.

Acetylcholine (ACh) is an evolutionarily conserved neurotransmitter that is widely distributed in the central and peripheral nervous systems and plays essential roles in multiple physiological processes. This review summarizes the full biological cycle of ACh, including its synthesis, vesicular storage, release, degradation, and reuptake, and discusses the regulatory mechanisms underlying its functions in the nervous system and peripheral organs. Through nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs), ACh is involved in central nervous system functions such as cognition, learning and memory, attention, arousal, reward, and decision-making, as well as peripheral processes including motor control, autonomic regulation, and immune modulation. In addition, ACh plays a pivotal role in the brain–body axis. At the central level, the nervous system regulates peripheral organ function through autonomic and neuroendocrine pathways. At the peripheral level, cholinergic signals derived from the enteric nervous system and immune cells convey information about the body’s internal state to the central nervous system through vagal and other afferent pathways, forming an important bottom-up regulatory network. Collectively, these findings indicate that ACh is not only a classical neurotransmitter but also a key molecular mediator of brain–body communication. A more comprehensive understanding of cholinergic signaling may provide new insights into physiological regulation and the pathogenesis of neurological, psychiatric, cardiovascular, and inflammatory diseases.