Pre- and post-synaptic roles of action potential activity in synapse elimination revealed by using ectopic neuromuscular junction formation by a foreign nerve.

The formation of the neuromuscular junction (nmj) is based on molecular cascades initiated by neural agrin as well as electrical activity in the neuromuscular structures. This review focuses on the latter factor, emphasizing the multiplicity of its mechanisms in the process of synapse elimination following initial polyneuronal innervation. Pre- and post-synaptic components of activity have in fact been identified through experiments on an adult model of nmj formation: ectopic reinnervation of the rat soleus muscle by the fibular nerve.

Activity-dependent vs. neurotrophic modulation of acetylcholine receptor expression: Evidence from rat soleus and extensor digitorum longus muscles confirms the exclusive role of activity.

Evoked electrical muscle activity suppresses the transcription of mRNAs for acetylcholine receptors in extrajunctional myonuclei. Muscle denervation or disuse releases such inhibition and extrajunctional receptors appear. However, in soleus muscles paralysed with nerve-applied tetrodotoxin, a restricted perijunctional region has been described where myonuclei remain inhibited, a finding attributed to nerve-derived trophic factor(s).

Adult rat motor neurons do not re-establish electrical coupling during axonal regeneration and muscle reinnervation.

Gap junctions (GJs) between neurons are present in both the newborn and the adult nervous system, and although important roles have been suggested or demonstrated in a number of instances, in many other cases a full understanding of their physiological role is still missing. GJs are expressed in the rodent lumbar cord at birth and mediate both dye and electrical coupling between motor neurons. This expression has been proposed to mediate: (i) fast synchronization of motoneuronal spike activity, in turn linked to the process of refinement of neuromuscular connections, and (ii) slow synchronization of locomotor-like oscillatory activity.

The timing of activity is a regulatory signal during development of neural connections.

In PNS and CNS remarkable rearrangements occur soon after the connections are laid down in the course of embryonic life. These processes clearly follow the period of developmental cell death and mostly take place during the very beginning of postnatal life. They consist in changes of the peripheral fields of neurons, marked by elimination of many inputs, while others undergo further maturation and strengthening.

Hebb-based rules of neural plasticity: are they ubiquitously important for the refinement of synaptic connections in development?

Neuronal death and suppression of functional synaptic inputs are well-known regressive events characterizing PNS and CNS development. In the CNS, participation of activity in synapse elimination has been known ever since the pioneering studies of Hubel and Wiesel, but only recently has a Hebb-based mechanism of spike synchrony versus asynchrony received unequivocal experimental support in the visual system. At the neuromuscular junction (NMJ), where synapse elimination was discovered, the specific function of the "timing of activity" was addressed by only one group of studies and did not receive widespread attention.

Spike timing plays a key role in synapse elimination at the neuromuscular junction.

Nerve impulse activity produces both developmental and adult plastic changes in neural networks. For development, however, its precise role and the mechanisms involved remain elusive. Using the classic model of synapse competition and elimination at newly formed neuromuscular junctions, we asked whether spike timing is the instructive signal at inputs competing for synaptic space.

Expression of small-conductance calcium-activated potassium channels (SK3) in skeletal muscle: regulation by muscle activity.

The type 3 small conductance calcium-activated potassium channel (SK3) is expressed in embryonic and adult denervated skeletal muscles where it contributes to hyperexcitability. This study aimed at determining the role of muscle activity in regulating SK3 channels. Soleus muscles of adult rats were denervated by cutting the sciatic nerve.

Synapse formation and elimination: role of activity studied in different models of adult muscle reinnervation.

Synapse competition and elimination are a general developmental process both in central and in peripheral nervous systems that is strongly activity dependent. Some common features regulate synapse competition, and one of these is an application to development of the Hebb's postulate of learning: repeated coincident spike activity in competing presynaptic inputs on the same target cell inhibits competition, whereas noncoincident activity promotes weakening of some of the inputs and ultimately their elimination. Here we report experiments that indicate that the development of muscle innervation (initial polyneuronal innervation and subsequent synapse elimination) follows the Hebb's paradigm.

Activity-dependent synaptic competition at mammalian neuromuscular junctions.

Synapse elimination is a widespread developmental process in the peripheral and central nervous system that brings about refinement of neural connections through epigenetic mechanisms. Here we describe recent advances concerning the role of the pattern of motoneuronal firing, synchronous or asynchronous, in neuromuscular synapse elimination.

Perinatal switch from synchronous to asynchronous activity of motoneurons: link with synapse elimination.

Synaptic competition is a basic feature of developing neural connections. To shed light on its dependence on the activity pattern of competing inputs, we investigated in vivo rat motoneuronal firing during late embryonic and early neonatal life, when synapse elimination occurs in muscle. Electromyographic recordings with floating microelectrodes from tibialis anterior and soleus muscles revealed that action potentials of motoneurons belonging to the same pool have high temporal correlation.