z .ghasemzadeh

In daily life, stress in one of the important and potent modulators of behaviour. Inhibitory or faciliatory effects of acute and chronic stress exposure on memory performance (acquisition, consolidation and retrieval) have shown in previous researches. Under such circumstances, the levels of (nor) epinephrine (NE) rapidly increases in the memory related area including hippocampus and amygdala. Along with NE, the hypothalamic-pituitary-adrenocortical axis activates. Glocorticoids (GCs) hormones are the main end-products of the HPA axis activation. In different animal models have been shown that NE and glocorticoids mediate the modulatory effect of stress on memory. Microglia that originally form in the yolk sac are immune cells in the central nervous system and act as the brain's first line of cellular defense against various pathogens. These cells release inflammatory mediators and neurotrophic factors and also phagocytes cellular debris. In addition, are also shown to play a role in the development of brain. During embryonic development, microglia remove apoptotic cells and regulate synaptic pruning. These cells play an essential role in regulating of synapse regeneration, neurogenesis, synaptic function, angiogenesis and myelination. They are dynamic cells in the adult brain and have the ability to rapidly change their morphology to properly respond to the functional needs of the brain. Microglia is activated in M1 and M2 phenotype. M1 microglia activation is induced by gamma interferon and LPS and promotes inflammation via release of inflammatory mediators such as tumor necrosis factor alpha (αTNF) and interleukins. M2 activation mainly is related to secretion of glucocorticoids, extracellular matrix proteins and anti-inflammatory cytokines. It has been reported that microglia as a key regulator of neuronal function have NE and GCs receptors, suggesting a critical role of these brain cells in modulating stress effects. Several lines of studies indicates that microglia regulate learning and memory via the formation and stability of synapses. Microglia actively contribute in synaptic pruning via classical complement cascade mechanism. Apoptotic, immature or poorly growing synapses are labeled with complement components, C1q and C3. Microglia recognize these complement components through the complement receptor CR3 and eliminate C1q and C3-labeled synapses. Microglia also detect and remove inactive synapses by the triggering receptor expressed on myeloid cells 2 (TREM2) consequently regulate brain connectivity and activity. Moreover, microglia regulatory negative feedback mechanism prevents neuron hyperactivity. Microglia play an important role in the stability of long-term potentiation. In addition, microglial fractalkine signaling is potentially involved in LTD. The number and morphology of hippocampal microglia is altered in response to chronic stress exposure thus consequently becomes reactive phenotype. This effect is mediated via stress hormones. Evidence show that stress also affect expression of microglial genes (cytokines, TNF-α and interleukins) that have regulatory role in learning and memory. Microglial–neuronal crosstalk which is crucial for memory processing is another site for stress-induced memory changes. Moreover, stress exposure alters glutamate transmission through negative effect on kynurenine pathway. These effects support the involvement of microglia in destructive effect of stress on memory. In this review article, focusing on newly published articles, we examine the role of microglia in synaptic plasticity, learning and memory, and especially the role of activated microglia in the effects of stress on learning and memory. By examining these processes, our aim is to provide an overview of the role of microglia in synaptic plasticity and learning and memory, and the possibility of using microglia targeting as a therapeutic method to improve cognitive deficits associated with stressful conditions