Spontaneous Activity Changes in Developing Barrel Cortex
Shingo Nakazawa, Yumiko Yoshimura, Masahiro Takagi, Hidenobu Mizuno, and Takuji Iwasato
(see pages 7637–7650)
Patterned spontaneous activity is required for proper formation of sensory maps in developing sensory pathways. In the developing somatosensory system of rodents, waves of spontaneous synchronous activity spread in the thalamus, and desynchronizing this activity disrupts patterning of the barrel cortex (Antón-Bolaños et al., 2019, Science 364:987). Within the barrel cortex itself, neurons in patches corresponding to future barrels show spontaneous synchronous activity on postnatal day 5 (P5), when the barrels are first forming. By P11, however, spontaneous activity in L4 becomes sparse and asynchronous. Nakazawa et al. used in vivo calcium imaging to investigate how these patterns develop and what causes the transition from synchronous to asynchronous activity in mice.
A patchwork pattern of synchronous activity similar to that seen at P5 was found in L4 as early as P1, before barrel structures were visible. These patches were larger and more overlapping at P1 than at P5, however. Surprisingly, rather than shifting gradually to a sparser, less synchronous activity pattern, synchronous spontaneous activity became more widespread, extending beyond individual barrels by P9. Nevertheless, by P11, spontaneous activity was sparse and asynchronous. Notably, whereas inhibiting neuronal activity in the ventrobasal thalamus blocked spontaneous activity in barrel cortex at P1 and P5, it did not alter barrel cortex activity at P9 or P11.
The density of dendritic spines greatly increases in mouse cortex during the second postnatal week, and Nakazawa et al. speculated that this may contribute to the transition from widespread synchronous to sparse asynchronous activity in barrel cortex. To test this, they expressed a dominant-negative form of the small GTPase Rac1 in cortical neurons starting on P7. Consistent with the authors' hypothesis, this not only reduced spine density in L4 at P11, but also significantly increased the occurrence of widespread synchronous activity at this age.
These results indicate that at least three forms of spontaneous activity occur in the developing barrel cortex. First, thalamic input drives synchronous activity in groups of neurons that will become incorporated into single barrels. After barrels form, synchronous activity occurs widely across barrels, independently of thalamic input. Activity becomes sparse and asynchronous as spine synapses become more abundant. How these phases of spontaneous activity affect developing circuits remains to be determined.
In the SOL muscle of SOD1G37R mice, galectine-3 (left panels) is upregulated in PSCs of denervated NMJs (top) but not in innervated NMJs (bottom). In right panels, postsynaptic sites at NMJ are red; presynaptic sites are green. See Martineau et al. for details.
Perisynaptic Schwann Cell Dysfunction in ALS Model
Éric Martineau, Danielle Arbour, Joanne Vallée, and Richard Robitaille
(see pages 7759–7777)
Amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness and paralysis resulting from motor neuron degeneration. The first step in this process is loss of neuromuscular junctions (NMJs), which occurs before symptom onset. Dysfunction in perisynaptic Schwann cells that surround NMJs might also contribute to ALS progression. These cells normally provide trophic support, and, after denervation, they promote recovery by phagocytosing cellular debris and extending processes that guide sprouting axons. Martineau et al. provide evidence that these functions are impaired in mice that express an ALS-linked mutant form of superoxide dismutase (SOD1G37R).
In response to synaptic activity, perisynaptic Schwann cells exhibit calcium transients stemming from the activation of muscarinic and purinergic receptors. Arbour and colleagues previously found that these transients were enhanced as a result of increased muscarinic signaling in SOD1G37R mice. But that study examined only fast fatigue-resistant and slow motor units of the soleus (SOL) muscle, which are generally more resistant to degeneration than fast fatigable motor units. The authors now report that in perisynaptic Schwann cells of fast fatigable motor units in the sternomastoid (STM) muscle, the amplitude of calcium transients is lower than normal as a consequence of decreased purinergic signaling. These responses returned to control levels by the time SOD1G37R mice exhibited motor impairment, however.
Perhaps more important for disease progression, upregulation of galectine-3, a marker of phagocytic glia, was blunted in perisynaptic Schwann cells in SOD1G37R mice. Furthermore, extension of Schwann cell processes and axon sprouting at denervated NMJs was lower than expected. Notably, both of these defects were more pronounced in the STM muscle than in the SOL muscle. Moreover, whereas galectine-3 upregulation and Schwann-cell process extension were restricted to denervated NMJs in the SOL muscle (as they are in wild-type mice), they occurred with equal frequency at denervated and fully innervated NMJs in the STM muscle.
These results support the hypothesis that defects in perisynaptic Schwann cells contribute to the progression of ALS partly by failing to promote reinnervation of denervated NMJs and partly by inappropriately assuming a repair phenotype at healthy NMJs. Future studies should elucidate the molecular mechanisms underlying these effects, including the extent to which early alteration of calcium signaling contributes to them.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
In this issue
