User:Anna Zelenska/sandbox

= Role of microglia in synaptic plasticity, memories formation and forgetting = Microglia are involved in a wide range of processes during brain development and in adult state, such as immune surveillance of the CNS, clearance of cellular debris, neuronal proliferation and differentiation, synaptic pruning, remyelination, secretion of neurotrophic factors, etc. Studies of recent years also provide evidence for the essential role of microglia in formation and retention of memories and in forgetting. Under normal physiological conditions in the brain, microglial processes are constantly motile and are found in close proximity to synapses in both early postnatal and adult cortex. . Recent studies have shown that microglia can influence brain wiring through the regulation of the number, maturation, and plasticity of synapses in processes of development of the CNS and throughout the life span.

Synaptic connections between engram cells are considered as substrates for memories storage; it has been shown that reactivation of engram neurons is essential for memory recall, while dissociation or weakening of connections between these cells leads to the forgetting of memories. During neurogenesis, dentate gyrus located in the hippocampus undergoes massive synaptic reorganization, which leads to the forgetting of hippocampus-dependent memories and the formation of new neural circuits. Moreover, it is currently known that dynamic remodeling of synapses occurs constantly throughout life, being associated with experience and learning and providing a potential mechanism of erasure of memories stored in these synaptic connections. Thus, mechanisms that contribute to synapse remodeling are critical to the flexibility of learning and memory.

Microglia-mediated phagocytosis and its role in forgetting
Among the first clues suggesting a role of microglia in synaptic pruning was the observation that phagocytic microglia is enriched in brain regions undergoing active remodeling of synapses, such as hippocampus, cerebellum, and the visual system. Different studies provide evidence that microglia-dependent synaptic elimination preferentially targets weak or less active synapses. It has been found that complement proteins specifically localize and bind to apoptotic, immature or weak developing synapses in the CNS, which are then recognized by complement receptors and consequently engulfed. Two complement proteins, C1q and C3, are predominantly produced by microglia or astrocytes, and ‘tag’ the appropriate synapses. C1q and C3 are recognized by the complement receptor CR3, which is exclusively expressed on microglia, mediating the phagocytosis of synapses. In line with this, disrupting microglia-specific CR3/C3 signaling resulted in persistent deficits in synaptic connectivity, which emphasizes a role of microglia in postnatal development and identify mechanisms by which microglia engulf and remodel developing synapses.

It has been recently shown that microglia depletion in mice undergoing stress-related training (contextual fear conditioning with weak foot electric shocks) prevented forgetting stress-related memories 35 days after training. Moreover, the authors confirmed that forgetting was mediated by microglia-dependent phagocytosis. Injection of mice with CD55, an inhibitor of both classical and alternative complement pathways, led to the retention of stress-associated memories and higher reactivation rate of engram cells compared with the control group. This study has also shown that microglia is involved in both adult neurogenesis-related and neurogenesis-unrelated forgetting of memories.

Another mechanism involved in microglia-mediated phagocytosis is dependent on CX3CR1, which is highly expressed in microglia. CX3CR1 knockout mice showed transient deficit in synaptic pruning, which suggests that locally released CX3CL1 might be important for recognition of synapses by microglia before or during engulfment and is necessary for normal brain development

Microglial BDNF in Synaptic Plasticity, Memory and Learning
The study revealed an important role of microglia in learning and memory formation by promoting learning-related synapse formation through brain-derived neurotrophic factor (BDNF) signaling. BDNF is a critical mediator of neuronal survival, differentiation, and plasticity, and although neurons are the predominant type of cells producing BDNF in the adult brain, it can also be detected in microglia, oligodendrocytes, and astrocytes. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in formation of synapses associated with learning new motor skills. Furthermore, genetic depletion of BDNF from microglia largely enhanced the effects of microglia depletion, and it has been found that BDNF produced by microglia increases neuronal TrkB phosphorylation, a key mediator of synaptic plasticity. These data indicate that microglial BDNF is an important factor for synaptic remodeling associated with learning and memory.

Role of microglia in memory quality
Several recent studies provided evidence for the role of microglia in memory quality, i.e. the ability to discriminate in similar context. For instance, it has been shown that microglia are involved in the control of memory quality via IL-33 signaling. It was shown that IL-33 is expressed by adult hippocampal neurons in an experience-dependent manner. Knockout of neuronal IL-33 or the microglial IL-33 receptor in mice reduced integration of newborn neurons, impaired synaptic plasticity and precision of remote fear memories. Moreover, IL-33 produced by neurons promotes microglial engulfment of the extracellular matrix (ECM), and its loss leads to impaired ECM engulfment and accumulation of ECM proteins in contact with synapses. These data shed light on mechanism through which microglia regulate experience-dependent synapse remodeling and promote memory consolidation.

Clinical significance
It is currently known that microglia activation, with production of proinflammatory cytokines and reactive oxygen species, or microglia dysfunction are associated with the progression of cognitive decline in ageing, neurodegenerative and neurological diseases such as Alzheimer’s disease, HIV-associated neurocognitive disorder, traumatic brain injury, and mental disorders including autism, stress and depression. Neuroinflammation is an important factor contributing to such neurodegenerative diseases as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease. Studies of Alzheimer’s disease showed decreased phagocytic activity of microglia due to the deficient triggering of IL-33 and receptor expressed on myeloid cells 2 (TREM2). Deficient phagocytic activity of microglia results in the accumulation of amyloid plaques and the dystrophy of neurons.

Being an essential regulator of synaptic connections and memory strength and precision, microglia is currently considered as a target for the treatment of cognitive decline associated with Alzheimer’s disease and other neurodegenerative diseases. Several companies are developing drug candidates targeting the activity of microglia in such diseases; however, the dynamic nature of microglia and complex interactions between neural and glial cells, as well as animal models with simplified pathogenesis of many human diseases of the CNS, differences between transcriptional profiles of microglia in mice and in humans, complicate design and testing of microglia-based therapeutics.