Let’s start by answering questions that may appear when you have read the title: What is synaptic pruning? What is a viral infection?
Synaptic pruning is a process that improves neural circuits by eliminating unnecessary and weak synapses [1]; at the same time, it can enhance cognitive functions, which include memory, learning, thinking, and feeling. A viral infection is a disease caused by a virus, not a bacterium [2].
Viral infections, which are the cause of many fatal and widespread diseases in the world, can disrupt synaptic pruning in the nervous system by altering synaptic protein expression and dysregulating mechanisms. These modulations may result in neuropathological outcomes and neurodevelopmental disorders, which are the consequences of either excessive synapse loss or synaptic retention. Thepresent article examines the relations between the most common viral infections and synaptic pruning.
Synaptic pruning, a subfield of neuroscience, was first observed in the 1970s with the importance of itsrole in embryonic development, maturation of neuronal networks, and maintaining a functionalbrain. Brain disorders like schizophrenia [3], autism[4], and epilepsy have connections with the downregulation of synaptic pruning. Downregulation is the reduction in the number of response cells to a stimulus. The changes in the synaptic plasticity and synaptic pruning can be affected by infectious agents,which also include viruses like human immunodeficiency virus (HIV), coronavirus(COVID-19), and influenza virus, etc [5].
Figure 1. Viruses and their effects on synaptic pruning.
Human immunodeficiency virus (HIV)
HIV, a neurotropic virus, which means it has a strong affinity for infecting neurons, and this infection can lead to cognitive and behavioural impairments in nearly half of the infected individuals [6]. This condition is related to HIV proteins like Tat, which disrupt neuronal processes by promoting the activation of N-methyl-D-aspartate receptors(NMDAs, channels permeable to Ca+2). This disruption can bring along mitochondrial dysfunction, oxidative stress, and high influx of calcium. The process is followed by neuroinflammation, the immune system’s protective response to the infections in the brain and spinal cord. This is one of the indirect mechanisms of HIV;it infects the immune system, then starts neuroinflammation, which causes the induction of excessive calcium ions. The abnormality of the calcium homeostasis leads to abnormal function of synaptic pruning. There is also a direct mechanismby which infection occurs directly in the nervous system [7].
Coronavirus
The virus is called Corona because the spike proteins give it the shape of a royal crown when examined under a high-powered electron microscope.Coronaviruses are one of the largest groups of viruses belonging to Nidovirales [8].
Being a member of that large group, SARS-CoV-2impacts the central nervous system, implicatingserious conditions like headache, diarrhea, anorexia,hallucinations, and epilepsy [9]. Infection with SARS-CoV-2 in cortical neurons disrupts the balance of ion channels. imbalance in the ion channels causes a reduction in the number of excitatory synapses and presynaptic proteins, leading to neuronal death and synapse loss [10].
The mechanism starts with the injection of the virus. This virus causes the induction of excessive cytokines, the chemical messengers of the body.Some of these cytokines reach the brain, overactivating the JAK\STAT pathway in microglia, which is the communication system of cells to respond to synapses [7]. These responses include trimming and pruning unnecessary synapses. This overactivation of the pathway makes microglia confused, which leads to trimming away healthy synapses while trimming unnecessary ones. Studies on brain tissue help to understand the consequences of synapse loss. People who died from severe infection of COVID-19 have shown neuronal damage, which is related to synapse loss [11].
Figure 2. JAK\STAT pathway responding to signals.
Influenza A virus
Influenza A virus contains a segmented single-stranded RNA genetic material, and it shows negative sense, which means its genetic material cannot be used to produce proteins immediately; cells need to replicate the positive form first to get proteins. In humans, the B type of the virus usually occurs amongthe four types A, B, C, and D, which have been identified. The virus not only infects humans, but it has also been seen in mammals and birds. Forexample, type A infects pigs and horses and can be considered the most dangerous [12].
The mechanism of Influenza shows similarities with the SARS-CoV-2 virus, but the neuronal damage mainly happens in the hippocampal circuits.Influenza mainly attacks the nose, bronchi, trachea,and lungs. Has the ability to easily spread itself through cough or sneeze. Infected lungs lead to the release of proinflammatory cytokines, the messengers of the immune cells that are released during infection or injury. That is followed by activation of microglia. As a result, microglia eliminate an excessive number of synapses, which causes a decrease in the dendritic spine density [13]. Dendritic growth plays an important role in the hippocampal region. It helps to enhance cognitive abilities such as memory and learning. Disruption in the hippocampal region causes cognitive problems [14].
Figure 3. The anterior hippocampus corresponds to a previous manual segmentation. Red: amygdala; green: anterior hippocampus; blue: caudate; violet: nucleus accumbens.
The brain is not free of infection. Viral modulation into synaptic pruning can leave lasting disruptions in neural circuits of the brain. By learning the mechanisms they use, we can mitigate their damage to our brain and body [7].
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