Synaptic Elimination

Synonyms

Synapse loss

Definition

Synaptic elimination is a process of brain development that reduces the number of synaptic contacts. The process is important for the formation of precise neural circuitry, which is necessary for proper brain functions. Synaptic contacts are generated in excess during the early phase of development. In subsequent stages, the redundant synapses are eliminated while the proper ones are strengthened to construct specific neural connections. Synapse elimination takes place in various neural tissues including cerebral cortex, cerebellum and neuromuscular junctions, and is supposed to be a general mechanism of the development of neural circuitry. The process of elimination is often regulated by neural activity so that active synapses are strengthened, whereas the inactive ones are weakened and ultimately eliminated.

Characteristics

Quantitative Description

The brain is not mature at birth and significant developmental events take place postnatally. During postnatal development, there is a period (critical period) of exuberant synapse formation followed by a period of synaptic “pruning” in the brain. The developmental profile of synapse number and density (number of synapses per unit volume) has been examined in various mammalian species including human.

In the primary visual cortex of monkey, synapse density increases rapidly around birth [1]. This period of synaptogenesis begins two months before birth, and the synaptic density reaches approximately the same level as that in adults. The rapid synaptogenesis continues for another two to three months after birth when the synaptic density reaches its maximum (about 90 synapses/100 μm³). The synapse density is maintained at this high level during the next two years. At puberty, however, synapse elimination begins and the synapse density rapidly decreases to the adult level (40–50 synapses/100 μm³) by five postnatal years. The postnatal development of synapse density reveals a similar profile, high synapse density during adolescence and lower density in maturity, in other cortical areas such as somatosensory, motor and limbic areas [2]. While the rapid synaptogenesis takes place concurrently in different cortical areas, the synapse elimination appears to begin earlier in the visual and somatosensory cortex than in the prefrontal cortex. However, the period of synapse elimination largely overlap with each other among cortical areas, and reach the adult level at the time of sexual maturity.

The development of cortical synapses follows a similar time course in the human brain. In human visual cortex, the synapse density shows a rapid increase at around two months of age and reaches the maximum at 8–10 months [3]. The synapse density then declines to the adult level at around ten years of age. In the frontal cortex, however, the beginning of synapse formation is delayed, and the synapse density gets to the maximum value at around two years of age. The high synapse density remains until eight years of age, and then slowly declines to the adult level at around 16 years. Thus, the rapid synaptogenesis and the following synapse elimination might take place at different times in different cortical areas in human [4].

The synapse elimination is regulated by experience-dependent mechanisms. If monkeys are raised without visual inputs by removing both eyes in utero, the decrease of a class of synapses in the visual cortex does not take place [5]. Furthermore, visual deprivation in one eye of developing animals leads to a strong suppression of cortical response to the deprived eye, and ultimately to the selective pruning of the input axons carrying information from the deprived eye [6].

Higher Level Processes

The elimination of redundant synapses is an important step for the construction of specific neural circuitry in the mature brain. Early formed neural connections tend to include aberrant projections. During development, the synapses made by such aberrant axons should be eliminated and the axon should finally retract. For example, refinement of neural connections by elimination of redundant synapses is well documented in skeletal muscles and autonomic ganglia [7]. Early in development, each muscle fiber and ganglionic neuron is innervated by multiple input axons from motor neurons and preganglionic neurons, respectively (Fig. 1, right).

Synaptic Elimination. Figure 1

Schematic representation of the rearrangement of neural connections during postnatal development. In the primary visual cortex (left), the ascending axons from the lateral geniculate nucleus provide inputs to cortical layer IV. The axons from two eyes (red and green, respectively) initially overlap and gradually segregate to occupy different cortical regions. The muscle fibers are innervated by multiple motor neurons at birth (right). The input axons lose their synaptic contacts to the inappropriate targets and project to single muscle fibers in the adult.

Thereafter, all but one input axon innervating the same target lose their synaptic contacts and retract, so that each muscle fiber and ganglionic neuron is innervated by a single axon in the adult. Although the synapses made with the inappropriate axons would disappear, the appropriate axons that will innervate the target in maturity grow in size and complexity to make more synaptic contacts. Thus, the development of neural networks is not a simple formation or elimination of synapses, but the redistribution of synapses so that each axon can focus its contacts to the appropriate targets.

A similar process also operates in the central nervous system. Input axons carrying information from each eye distribute separately in the primary visual cortex of higher mammals including cats, monkeys and humans [8] (Fig. 1, left). In young animals, however, the input axons from two eyes widely spread over the visual cortex and overlap with each other. The input axons gradually retract from inappropriate cortical territory and obtain the adult-like segregated distribution. In the cerebellum of newborn animals, the Purkinje cells are innervated by multiple climbing fibers that originate in the inferior olive [9]. During development, redundant climbing fibers are eliminated and single fibers innervate each Purkinje cell.

Process Regulation

The synapse elimination is largely regulated by mechanisms depending on neural activity. The developmental refinements of neural circuitry in various brain areas show that the competition between inputs plays an important role in determining which synapse should be eliminated (activity-dependent synaptic competition).

The direct observation of the process of synapse elimination in neuromuscular junctions offers a great deal of insight into the mechanisms of the process [7]. In the mouse neck, each muscle fiber receives axonal innervations from several motor neurons at birth. The number of innervations reduces in the following two weeks and each muscle fiber begins to receive single input. Before the withdrawal of redundant axon terminals, synapses on them reveal a functional weakening. Synaptic potentials recorded in the developing muscle fibers show that each of the multiple inputs has strong synaptic effects, enough to cause muscle contraction at birth, and the strength of each synaptic input is often indistinguishable from each other. Therefore, it is difficult to predict which input would subsequently monopolize the fiber. The input that is going to be eliminated ultimately becomes gradually weaker before any sign of retraction could be observed in the presynaptic terminals. The weakening of synaptic potentials is caused by a reduction in neurotransmitter release and by a reduction in postsynaptic receptor density. The physiological synapse elimination is followed by axonal withdrawal of weak inputs.

Synaptic interactions play a key role in determining which input should be eliminated. If neural activity of motor neuron axons is blocked pharmacologically, redundant axons do not retract and multiple innervations persist. Suppression of synaptic interactions at the neuromuscular junctions by blocking acetylcholine (ACh) receptors also prevents the input elimination. Thus, neural activity and the following synaptic interactions are necessary for the synapse rearrangements (activity-dependent synaptic rearrangement). In addition, if a small part of a single neuromuscular junction, which is innervated by one axon, is functionally blocked by applying an irreversible blocker of the postsynaptic ACh receptors, the ACh receptors gradually disappear only in the blocked region. Subsequently, the axon terminals innervating the blocked region withdraw as observed in natural development. On the other hand, blocking ACh receptors in the entire area of a single neuromuscular junction does not induce synapse elimination. Thus, synapse inactivation can lead to elimination of the synapse only when the other synapses are active, suggesting that local imbalance of input strength is an important factor to initiate synapse elimination. The synaptic interactions at active synapses might generate suppressive signals in the postsynaptic cells that can destabilize inactive synapses in the surrounding region, together with supportive signals that maintain the activated synapse. Although the molecular machinery of such intercellular signaling is yet to be characterized, several protein kinases and phosphatases might be involved in the process. For example, in mutant mice in which protein kinase C (PKC)-gamma is genetically inactivated, the elimination of multiple innervations of cerebellar Purkinje cells by climbing fibers, as mentioned above, is markedly prevented [10]. Thus, the activity of PKC is essential for normal elimination of redundant climbing fibers.

The relative strength of inputs also guides the rearrangement of input axons in the visual system [8]. Blocking visual inputs from one eye induces a strong suppression of the cortical responses to the eye, followed by a significant retraction of input axons serving the eye. If the visual inputs from both eyes are blocked, however, the suppression of cortical responses is limited and the input axons are maintained.

Pathology

Abnormal synapse elimination prevents the construction of normal neural circuitry and is supposed to underlie various psychiatric disorders, such as fragile X syndrome and schizophrenia.