Regulation of synaptogenesis and control of synaptic maintenance and elimination

The living brain constantly remodels and modifies its cellular networks. Throughout life, synapses continuously appear, strengthen, weaken or die. These processes underlie the adaptation of the brain to the constantly changing external environment and, in particular, represent what we know as learning and memory. For many years the process of synaptogenesis, maintenance and elimination of the synaptic contacts was considered to be solely neuronal responsibility; only very recently it has become apparent that glial cells (astrocytes in the CNS and Schwann cells in the PNS) control the birth, life and death of synapses formed in neuronal networks.

In general, the life cycle of the synapse proceeds through several stages: (1) formation of an initial contact between presynaptic terminal and postsynaptic neurone; (2) maturation of the synapse, when it acquires its specific properties, in particular the neurotransmitter modality; (3) stabilization and maintenance, which preserve the strong connections; and (4) elimination. In fact, the last stage may follow each of the preceding ones, and many synapses are eliminated before entering the stabilization phase.

The major wave of synaptogenesis in the mammalian brain starts shortly after birth, and lasts for several weeks in rodents and for a much longer period in humans. This wave of massive (as hundreds of billions of synapses have to occur within a relatively short time span) synaptogenesis precisely follows the massive generation of mature astrocytes, which happens during the perinatal period. This sequence of events is not coincidental as indeed astrocytes assist synapse appearance.

Synaptogenesis may occur in purified neuronal cultures, albeit at a relatively low rate; addition of astrocytes into this culture system dramatically (about seven times) increases the number of synapses formed. This increase in synaptic formation strictly depends on cholesterol, produced and secreted by astrocytes; cholesterol serves most likely as a building material for new membranes, which appear during synaptogenesis; in addition, cholesterol may be locally converted into steroid hormones, which in turn can act as synaptogenic signals. Glial cells also affect synaptogenesis through signals influencing the expression of a specific protein, agrin, essential for synapse formation.

After new synapses are formed, astrocytes control their maturation through several signalling systems affecting the postsynaptic density. In particular, introduction of astrocytes into neuronal cell cultures boosts the size of post-synaptic responses by increasing the number of post-synaptic receptors and facilitating their clustering. In contrast, removal of astroglial cells from neuronal cultures decreases the number of synapses. In part, these effects are mediated by several soluble factors released by astrocytes, although direct contact between glial and neuronal membranes also exerts a clear influence (of yet unidentified nature) on synapse maturation. Several distinct soluble factors have been identified that are released by glial cells and affect synapse maturation. One of them is tumour necrosis factor a (TNFa), which regulates the insertion of glutamate receptors into post-synaptic membranes; another one is activity-dependent neurotrophic factor (ADNF), which, after being secreted by astrocytes, increases the density of NMDA receptors in the membrane of neighbouring postsynaptic neurones. In chick retina, Müller glial cells control the expression of M2 muscarinic ACh receptors in retinal neurones through a hitherto unidentified protein.

Astrocytes may also limit the number of synapses that appear on a given neurone, as astroglial membranes ensheathing the neurolemma prevent the formation of new synaptic contacts. Astroglial cells can also be involved in the elimination of synapses in the CNS, the process which underlies the final tuning and plasticity of the neuronal inputs. This may be achieved by secretion of certain factors or proteolytic enzymes, which demolish the extracellular matrix and reduce the stability of the synaptic contact. Subsequently, astroglial processes may enter the synaptic cleft and literally close and substitute the synapse.

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Responses

  • Priscilla
    How cholesterol control synaptogenesis?
    5 years ago

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