Hypothalamic Integration: Organization of the Paraventricular and Supraoptic Nuclei

We describe the formation, maturation, elimination, maintenance, and regeneration of vertebrate neuromuscular junctions (NMJs), the best studied of all synapses. The NMJ forms in a series of steps that involve the exchange of signals among its three cellular components--nerve terminal, muscle fiber, and Schwann cell. Although essentially any motor axon can form NMJs with any muscle fiber, an additional set of cues biases synapse formation in favor of appropriate partners. The NMJ is functional at birth but undergoes numerous alterations postnatally. One step in maturation is the elimination of excess inputs, a competitive process in which the muscle is an intermediary. Once elimination is complete, the NMJ is maintained stably in a dynamic equilibrium that can be perturbed to initiate remodeling. NMJs regenerate following damage to nerve or muscle, but this process differs in fundamental ways from embryonic synaptogenesis. Finally, we consider the extent to which the NMJ is a suitable model for development of neuron-neuron synapses.

Development of the vertebrate neuromuscular junction.

A full-length clone coding for the rat alpha 7 nicotinic receptor subunit was isolated from an adult brain cDNA library and expressed in Xenopus oocytes. A significant proportion of the current through alpha 7-channels is carried by Ca2+. This Ca2+ influx then activates a Ca(2+)- dependent Cl- conductance, which is blocked by the chloride channel blockers niflumic and fluflenamic acid. Increasing the external NaCl concentration caused the reversal potentials for the alpha 7-channels and the Ca(2+)-dependent Cl- channels to be shifted in opposite directions. Under these conditions, agonist application activates a biphasic current with an initial inward current through alpha 7- channels followed by a niflumic acid- and fluflenamic acid-blockable outward current through Ca(2+)-dependent Cl- channels. A relative measure of the Ca2+ permeability was made by measuring the shift in the reversal potential caused by adding 10 mM Ca2+ to the external solution. Measurements made in the absence of Cl-, to avoid artifactual current through Ca(2+)-activated Cl- channels, indicate that alpha 7- homooligomeric channels have a greater relative Ca2+ permeability than the other nicotinic ACh receptors. Furthermore, alpha 7-channels have an even greater relative Ca2+ permeability than the NMDA subtype of glutamate receptors. High levels of alpha 7-transcripts were localized by in situ hybridization in the olfactory areas, the hippocampus, the hypothalamus, the amygdala, and the cerebral cortex. These results imply that alpha 7-containing receptors may play a role in activating calcium-dependent mechanisms in specific neuronal populations of the adult rat limbic system.

https://www.jneurosci.org/content/jneuro/13/2/596.full.pdf

Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium

Experience exerts a profound influence on the brain and, therefore, on behavior. When the effect of experience on the brain is particularly strong during a limited period in development, this period is referred to as a sensitive period. Such periods allow experience to instruct neural circuits to process or represent information in a way that is adaptive for the individual. When experience provides information that is essential for normal development and alters performance permanently, such sensitive periods are referred to as critical periods. Although sensitive periods are reflected in behavior, they are actually a property of neural circuits. Mechanisms of plasticity at the circuit level are discussed that have been shown to operate during sensitive periods. A hypothesis is proposed that experience during a sensitive period modifies the architecture of a circuit in fundamental ways, causing certain patterns of connectivity to become highly stable and, therefore, energetically preferred. Plasticity that occurs beyond the end of a sensitive period, which is substantial in many circuits, alters connectivity patterns within the architectural constraints established during the sensitive period. Preferences in a circuit that result from experience during sensitive periods are illustrated graphically as changes in a ''stability landscape,'' a metaphor that represents the relative contributions of genetic and experiential influences in shaping the information processing capabilities of a neural circuit. By understanding sensitive periods at the circuit level, as well as understanding the relationship between circuit properties and behavior, we gain a deeper insight into the critical role that experience plays in shaping the development of the brain and behavior.

https://faculty.washington.edu/losterho/knudson_critical_periods_jcn_2004.pdf

Sensitive Periods in the Development of the Brain and Behavior

The specificity of synapses in the mammalian brain cannot possibly be accounted for by one-to-one biochemical matching. The alternative proposed in this article is that connections are genetically specified between classes of cells, but the final wiring pattern depends on the refinement of those collections by selective stabilisation during neuronal activity.

Selective stabilisation of developing synapses as a mechanism for the specification of neuronal networks.

Some observations on the binding patterns of α-bungarotoxin in the central nervous system of the rat

SNAKE α-toxins have high specificity and affinity for nicotinic receptors, and have been used widely for the characterisation of peripheral acetylcholine receptors of electric organs and skeletal muscle. In some cases autoradiography has shown the extent and local distribution of bound neurotoxins1–5. Although α-bungarotoxin (α-BTX) does not pass the blood-brain barrier and therefore does not enter the central nervous system (CNS) to a measurable extent6, central nicotinic acetylcholine receptors may bind α-toxins in vitro, and several investigators have used this toxin to characterise brain receptors7–9. Its specificity for central nicotinic receptors has been inferred not only from its peripheral action, but also from cytological and pharmacological observations: binding activity is highest in synaptosomal preparations, and is inhibited by various nicotinic drugs. Studies on the localisation of toxin-binding sites in brains, not so far reported, would be valuable, not only to corroborate neurotoxin specificity, but also to provide information on the regional distribution of nicotinic receptor sites in the CNS.

Autoradiographic localisation of α-bungarotoxin-binding sites in the central nervous system

The electron microscopic autoradiographic localization of α-bungarotoxin binding sites within the central nervous system of the rat

Transcriptional activity of acetylcholine receptor subunit genes was investigated in innervated and denervated chick skeletal muscle. The sciatic nerve of 3-d-old White Leghorn chicks was sectioned unilaterally; after various intervals, nuclei were isolated from operated and sham-operated animals, and run-on assays performed. Nuclei were incubated with 32P-UTP, and total RNA was extracted and hybridized onto filters containing an excess of subunit-specific DNA. Specific transcripts were detected by autoradiography and quantitated densitometrically. A sharp increase in transcriptional activity was observed to begin approximately 1/2 d after the operation and peak 1 d later when transcriptional rates reached approximately seven-, six-, and fivefold control levels for the alpha-, delta-, and gamma-subunit genes, respectively. The specificity of the effect was ascertained by normalization to total RNA synthesis and by the demonstration that several nonreceptor genes respond differently to denervation. These results suggest that a denervation signal reaches the genome to induce receptor expression. In addition, since the increase in mRNA levels significantly exceeds what can be accounted for by increased gene activity, posttranscriptional effects are suggested.

/pdf/skeletal-muscle-denervation-activates-acetylcholine-receptor-8iuww1av1r.pdf

Skeletal muscle denervation activates acetylcholine receptor genes.

The drug binding properties of an α-bungarotoxin-binding component in a crude membrane preparation from whole rat brain were investigated by analyzing the effects of various neuroactive drugs on the rate of toxin binding. High affinities were found for nicotinic ligands such as d-tubocurarine, nicotine, gallamine, and dihydro-β-erythroidine, whereas interaction with choline and muscarinic compounds was observed to be weak and presumably due to nonspecific electrostatic forces. Little interaction was seen with other putative neurotransmitters. No evidence was obtained for more than one type of toxin binding site. The findings are interpreted as supporting the notion that the α-bungarotoxin-binding macromolecule in the central nervous system is a nicotinic acetylcholine receptor.

Jakob Schmidt

Papers

Some observations on the binding patterns of α-bungarotoxin in the central nervous system of the rat

Autoradiographic localisation of α-bungarotoxin-binding sites in the central nervous system

The electron microscopic autoradiographic localization of α-bungarotoxin binding sites within the central nervous system of the rat

Skeletal muscle denervation activates acetylcholine receptor genes.

Drug binding properties of an alpha-bungarotoxin-binding component from rat brain.