The Neuron Doctrine Revisited

Electron microscopy conclusively shows that nerve cells are separate, but the neuron doctrine needs careful revision. Indeed, this has gone forward. Four issues spurred its reevaluation.

1. Gap Junctions, Cell-to-Cell Influences, and Electrical Synapses

Small, roughly circular plaques (0.1 mm to many micrometers across) of intimate apposition (2-3 nm) unite the membranes of epithelial cells. Here, tiny membrane particles (connexons) with minute pores (<2nm) in each membrane and in register permit the flow of ions and small molecules (amino acids, cyclic AMP, tracers) between cells. Such a contact is a gap junction, nexus, or communicating junction. The last term is definitive: they permit cell-to-cell percolation of nucleotides and peptides that may coordinate cellular activity. They also offer low-resistance electrical coupling of adjacent cells, as in embryonic tissues. In neural development, cell-to-cell communication by gap junctions in epithelial tissues plays a role in major events, as in gastrulation and neural plate closure.

For a time, gap junctions challenged the second tenet of the neuron doctrine. They allowed chemical commerce between neurons and united them electrically. But controversy subsided. Though present in a few neurons in a few places in the adult and more widely encountered in the early CNS, such areas of interaction between separate cells do not undermine the unitary nature of neurons.

2. Versatility of Neuronal Processes and Complexity of the Neuropil

An old problem in studying neurons (especially invertebrate ones) is identifying their extensions as dendrites or axons. Some processes play both roles. Such versatility violates the law of dynamic polarization tacked on to the neuron doctrine: that dendrites and cell body receive impulses and the axon and its terminals conduct them away and deliver them elsewhere. But the parts of neurons are adaptable. Dynamic polarization was based on a neuron considered to be typical: the motor neuron.

Today, we know that the neuronal surface is a mosaic of receptor and effector parts and that local circuits with different polarizations need no spikes but only graded potentials to function. Cajal's law must be viewed in perspective. It was a great step in

Neuronal Fiber Tangles

Figure 17 Glomeruli, resembling renal capillary glomeruli and long known in the cerebellum and olfactory bulb; many more complex tangles of intricately intertwined and synapsing neuronal processes of multiple origin are now recognized elsewhere. The interactions of processes in many of these knots are not known, but as shown in this schematic drawing, some provide for divergence or convergence of information. At left, a glomerulus in the cerebellar cortex centered on a single mossy fiber axon terminal; at right, a glomerulus in the thalamic pulvinar centered on a single departing dendrite. From Jay B. Angevine, Jr., (1988) Dendrites, axons and synapses, BNI Quarterly 4(2), 9-19. after T. Bullock, R. D. Orkand, and A. D. Grinell (illustration by Steven J. Harrison) by permission of Barrow Neurological Institute.

Figure 17 Glomeruli, resembling renal capillary glomeruli and long known in the cerebellum and olfactory bulb; many more complex tangles of intricately intertwined and synapsing neuronal processes of multiple origin are now recognized elsewhere. The interactions of processes in many of these knots are not known, but as shown in this schematic drawing, some provide for divergence or convergence of information. At left, a glomerulus in the cerebellar cortex centered on a single mossy fiber axon terminal; at right, a glomerulus in the thalamic pulvinar centered on a single departing dendrite. From Jay B. Angevine, Jr., (1988) Dendrites, axons and synapses, BNI Quarterly 4(2), 9-19. after T. Bullock, R. D. Orkand, and A. D. Grinell (illustration by Steven J. Harrison) by permission of Barrow Neurological Institute.

understanding neuronal activity, but it cannot account for the almost limitless interactions between neurons.

Related problems are glomeruli (Fig. 17), which are knots of neuronal processes of diverse morphology and origin in which group synapses (rather than the familiar paradigm of one-on-one) are the rule and complex transactions of many cells, near and afar, are afoot. Here the independence of neurons is diminished, but not abrogated, by the complexity of the neuropil, the feltwork of neuronal and glial processes in which most synapses are found and most CNS business is transacted. Awareness of the epithelial nature of nervous tissue helps to explain these regions of multineuronal interaction.

3. Neuronal Teamwork and Distributed Systems

A critique of the functional tenet of the neuron doctrine comes from the growing awareness that the nervous system employs groups of neurons, not necessarily all in one place, to perform its tasks, and not single cells themselves. Striking examples are the progressive feature analyses by sensory systems of the CNS (notably the visual), the cooperative interplay of neurons at all levels of the motor system, and the communal organization and stepwise connections of the cerebral cortex. A fitting term for this team concept of neuronal function is distributed system. As a key principle that is crucial to understanding cognitive functions and disorders, it does not impugn the individuality of neurons in any respect. However, it lessens their individual importance as determinative functional or gnostic units.

4. Transneuronal Degeneration

Neuronal responses to axon interruption include degenerative changes in the severed axon and its investments, as well as reparative changes in the cell body. Undamaged neurons nearby do not react, nor does the degeneration usually involve the postsynaptic cell, with certain major exceptions: atrophy of skeletal muscle is a familiar consequence of denervation. These results illustrate tenets one and four: the anatomical individuality of neurons and the trophic importance of their cell bodies. But with a century gone by and better methods for evaluating and following up effects of injury upon neurons, the concept of a single neuron as the trophic unit is hardly tenable.

Transneuronal degeneration is now well-recognized. It was first noted in pathways in which a given neuron largely depends on another for its input. In the visual system, cells of the thalamic lateral geniculate nucleus degenerate after lesions to the retina, where the ganglion cells that project to them lie. Transneuronal effects are now known in many neuronal sequences in the CNS and PNS. Even more remarkable is that transynaptic effects of injury or disuse may extend in either direction (retrograde and orthograde) and involve neurons one or more than one synapse removed (primary, secondary, tertiary, etc.). Neurons in circuits seem to depend on one another in ways that go beyond receipt and delivery of impulses. Their metabolic equilibrium may derive, in part and varied measure, from their interactions. These possibilities are relevant to interpreting experimental lesions or treating neurologic diseases. Insights on the factors underlying these trophisms may explain how the nervous system maintains itself and what it could do (with assistance) to compensate for injury or cell loss.

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