Depression is a serious neuropsychiatric disease affecting an increasing number of people worldwide. Cognitive deficits (including inattention, poor memory, and decision-making difficulties) are common in the clinical picture of depression. Cognitive impairment has been hypothesized to be one of the most important components of major depressive disorder (MDD; referred to as clinical depression), although typical cognitive symptoms are less frequent in people with depression than in people with schizophrenia or bipolar disorder (BD; sometimes referred to as manic-depressive disorder). The importance of α-Klotho in the aging process has been well-documented. Growing evidence points to the role of α-Klotho in regulating other biological functions, including responses to oxidative stress and the modulation of synaptic plasticity. It has been proven that a Klotho deficit may contribute to the development of various nervous system pathologies, such as behavioral disorders or neurodegeneration. Given the growing evidence of the role of α-Klotho in depression and cognitive impairment, it is assumed that this protein may be a molecular link between them. Here, we provide a research review of the role of α-Klotho in depression and cognitive impairment. Furthermore, we propose potential mechanisms (related to oxidative stress and glutamatergic transmission) that may be important in α-Klotho-mediated regulation of mental and cognitive function.

Depressive disorders (DDs) are an increasingly common health problem that affects all age groups. DDs pathogenesis is multifactorial. However, it was proven that stress is one of the most important environmental factors contributing to the development of these conditions. In recent years, there has been growing interest in the role of the glutamatergic system in the context of pharmacotherapy of DDs. Thus, it has become increasingly important to explore the functioning of excitatory synapses in pathogenesis and pharmacological treatment of psychiatric disorders (including DDs). This knowledge may lead to the description of new mechanisms of depression and indicate new potential targets for the pharmacotherapy of illness. An excitatory synapse is a highly complex and very dynamic structure, containing a vast number of proteins. This review aimed to discuss in detail the role of the key postsynaptic proteins (e.g., NMDAR, AMPAR, mGluR5, PSD-95, Homer, NOS etc.) in the excitatory synapse and to systematize the knowledge about changes that occur in the clinical course of depression and after antidepressant treatment. In addition, a discussion on the potential use of ligands and/or modulators of postsynaptic proteins at the excitatory synapse has been presented.