Mechanisms underlying spontaneous patterned activity in developing neural circuits

Abstract

Patterned, spontaneous activity occurs in many developing neural circuits, including the retina, the cochlea, the spinal cord, the cerebellum and the hippocampus, where it provides signals that are important for the development of neurons and their connections. Despite there being differences in adult architecture and output across these various circuits, the patterns of spontaneous network activity and the mechanisms that generate it are remarkably similar. The mechanisms can include a depolarizing action of GABA (gamma-aminobutyric acid), transient synaptic connections, extrasynaptic transmission, gap junction coupling and the presence of pacemaker-like neurons. Interestingly, spontaneous activity is robust; if one element of a circuit is disrupted another will generate similar activity. This research suggests that developing neural circuits exhibit transient and tunable features that maintain a source of correlated activity during crucial stages of development.

Figure 1. Homeostatic regulation of spontaneous network activity in the chick spinal cord

When a part of the spinal cord network is blocked, activity becomes temporarily less frequent, but recovers to pre-block levels. Here we provide schematics of the changes that take place after activity blockade. a. Schematic of the circuits that mediate activity in the developing spinal cord. Neurons are color-coded by the transmitter they release. ACh, acetylcholine, blue; Glu, glutamate, green; Gly, glycine, pink; GABA, pink. b. Motor neurons provide a crucial drive in the generation of activity. They receive input from other motor neurons and from interneurons. nAChR, nicotinic acetylcholine receptor; GABA_A-R, GABA_A receptor; iGluR, ionotropic glutamate receptor. c. When GABA_A receptors are blocked in ovo (left), activity becomes temporarily less frequent but recovers . After 12 hours of GABA_A-R blockade, motor neurons become more excitable, an effect that is mediated by an increase in the density of sodium current and a decrease in the density of potassium current (right). Bottom: schematics illustrating an increase in motor neuron excitability, with the bottom curve showing current injection into a motor neuron, and the top curve showing membrane potential. A more excitable motor neuron fires more action potentials in response to the same stimulus (right). I_Na, sodium current, represented by sodium channels; I_K, potassium current, represented by potassium channels. d. When GABA_A receptors are blocked for long periods (24–48 hours) glutamatergic and GABAergic postsynaptic currents in motor neurons increase in size. The exact mechanisms underlying this increase in postsynaptic current are not fully understood, but are schematized here as increases in the number of glutamate and GABA_A receptors.

Figure 2. Homeostatic regulation of spontaneous network activity in the mammalian retina

In the absence of a requisite circuit component, the retina regresses to the previous wave-generating mechanism. Here we provide schematics of the circuits that mediate retinal waves at different ages, including the changes that are thought to take place when one form of activity is disrupted. a. Perinatally in mice, waves are mediated by a non-synaptic circuit, thought to be mediated by gap junction coupling (inset). Here the coupling is shown to be between retinal ganglion cells, although the location of the relevant coupling is not known. b. During the first postnatal week, starburst amacrine cells (blue) form synaptic connections with other starburst amacrine cells and retinal ganglion cells (gray). Retinas from mice lacking acetyl choline (Ach; bottom inset) exhibit non-synaptic waves, potentially through a reactivation of non-synaptic connections that mediate network activity in the perinatal period (see panel a). Furthermore, blocking nAChRs soon after the onset of cholinergic waves leads to the reappearance of non-synaptic waves. c: In the few days before eye opening in mice, when glutamatergic interneurons begin to form synapses with their postsynaptic targets, waves are mediated by glutamatergic circuits. Inset: Glutamatergic bipolar cells (green), which make glutamatergic synapses onto amacrine and ganglion cells and have no direct connections with each other, release glutamate that is detected both synaptically and extrasynaptically. After the first postnatal week, starburst cells no longer express nAChRs. Retinas from mice in which bipolar cells do not release glutamate (bottom inset) exhibit waves that are mediated by the cholinergic network.