Grey Matters: From Biochemical Synapse to Bioethical Syntax

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The synapse is a specialized junction through which neurons—the brain’s fundamental cellular units—signal other cells. An examination of patterns of neural transmission at the synapse provides an interesting small-scale paradigm for considering principles of effective and ineffective communication among and within human communities. Following a general description of the synapse, this essay will draw parallels to larger realms of human ethical communication.

A typical synapse consists of a presynaptic nerve terminal and a postsynaptic density separated by a narrow synaptic cleft. The presynaptic terminal buds from the tip of an axon, which is a long, slender projection of a neuron designed to conduct an electrical impulse known as an action potential. Vesicles filled with neurotransmitters lie docked at the presynaptic terminal. The arrival of an action potential produces an influx of calcium ions, which triggers a biochemical cascade culminating in fusion of the vesicles with the cell membrane and release of their contents into the synaptic cleft. Neurotransmitters, such as norepinephrine, acetylcholine, dopamine, glutamine, or gamma-aminobutyric acid, which vary depending on the type of synapse, act as signalling molecules that diffuse across the synaptic cleft and bind to their target receptors to produce a transsynaptic effect. Breakdown or reuptake of the neurotransmitter terminates the signal.

The adjacent neuron’s postsynaptic membrane appears as an elaborate, thickened complex of interlinked proteins gathered on the surface of a dendrite, which is one of the many arborizing extensions of a neuron. Neurotransmitter receptor binding alters the electrical potential of the dendritic membrane, which processes spatially and temporally the incoming barrage of synaptic impulses to form a signal directed toward the cell body. The dendrite receives both excitatory and inhibitory synaptic inputs. Once a sufficient number of receptor binding events occurs and threshold is reached, the postsynaptic neuron then fires an action potential. That momentary electrochemical flux becomes one nod from one neuron among the brain’s hundred billion.[1],[2]

Exquisitely precise networks of highly differentiated neurons integrate the signals flowing from synapse to synapse. In all there are approximately 160 trillion synapses in the adult human cerebral cortex.[3] A cubic millimeter of human cerebral cortex contains as many as a billion synapses. The brain’s internal communication network of synapses underlies its capacity to interpret, reflect upon, and interact with the external world and communicate with other persons.

Despite the brain’s vast number of dynamically interconnected neurons, it rarely descends into internal anarchy. Like musical instruments arranged in an orchestra, cortical neurons precisely lined in layers and columns listen for their cues and may collect input from thousands of other neurons before breaking silence. Many regions of the brain are functionally organized into delicate systems of checks and balances. Groups of neurons specialized to perform a specific function bounce information to complementary groups which then reply with feedback. These neuronal systems engage in planning, modeling or rehearsing exercises so that the coordinated response is finely tuned. From this symphony of synapses arise perception, thought, language, emotion, reasoning, belief and decision. The well-functioning synaptic brain draws from various knowledge resources within its memory banks, heeds its history, studies the signs of external reality, follows tested principles and anticipates outcomes. Perhaps the synapse with its robust relationships holds lessons in teamwork that could be instructive to the medical profession, bioethical discourse, and society at large.

The brain’s capacity to retain memory has been linked to synaptic plasticity. There is evidence that dynamic remodeling of the synapse, growth of new synaptic connections, and strengthening or weakening of existing synaptic connections underlie learning and memory as well as the development of some chronic sensitized pain and anxiety states.[4],[5] This synaptic flexibility entails benefits and risks similar to those encountered in the dynamics of interpersonal, intercultural and international human relationships. Individuals may choose to revise and strengthen favorable habits of communication in ways that promote healthy communication and minimize misunderstanding among persons. Society may choose to develop and reshape institutional systems of information sharing in ways that promote rather than frustrate human flourishing.

There is an intricate division of labor within the brain. Some neurons are tonically active, imparting through their synapses a steady, consistent message. Other neurons are phasic, waiting their turn until the right time to fire synaptic bursts of information. Still other neurons are fast-spiking. One might expect that fast-spiking neurons would be hair-trigger sentinels that respond promptly to novelty or potential danger and signal an immediate alarm, but that supposition would be incorrect. Fast-spiking neurons, in fact, are inhibitory.

Approximately 20% of cortical neurons inhibit rather than excite their neighboring neurons.[6] Synaptic inhibition is essential to cortical processing, and inhibitory neurons are especially diverse in morphology and function.[7],[8] Inhibitory interneurons in the somatosensory cortex, for example, selectively suppress irrelevant input, filtering out incidental distractions and unchanging sensory stimuli.[9] This allows the brain to focus. The brain, it would seem, values restraint. It values restraint not with the goal of inaction, but rather with the aim of achieving a controlled balance of calmness and intentionality.

Bioethics also expresses at times inhibitory judgments. Ethical principles necessarily impose certain limits on what should be done with biotechnology in the responsible service of human interests. In Oakland, California several years ago, a scientist attending the Center for Bioethics and Culture conference on Technosapiens asked a panel of bioethicists, “Must bioethics always say no?” This author’s reply was, “Well, no.”

Inhibitory systems such as those in the frontal lobes exert judicious control over subordinate brain systems which, if not restrained, could lead to unbridled and abnormal behavior. The famous case of Phineas Gage illustrates this point. Gage, a previously capable and even-tempered railroad construction foreman, sustained a devastating injury to his left frontal lobe when an explosion sent a metal rod through his skull. Following the accident, Gage became impatient, capricious, irreverent, profane, unable to process his emotions or to assess the future consequences necessary to make rational plans.[10]

Pathological activity at the level of the synapse is also instructive. Impaired release of a needed message may produce a null effect. Botulinum toxin, for example, blocks the release of the neurotransmitter acetylcholine from presynaptic nerve endings at the neuromuscular junction, causing paralysis. In other situations, incoherent neuronal signalling may generate an inconsistent effect. Antibodies to the acetylcholine receptor in myasthenia gravis, for example, block the arrival of the neurotransmitter on the postsynaptic terminal, causing intermittent or fatiguable weakness. At the level of ethics, silence in response to injustice can weaken society.

Synaptic overstimulation can be as detrimental as understimulation. Cocaine, for example, interferes with the synaptic reuptake of the neurotransmitters dopamine, norepinephrine and serotonin, leading to an excessive amount of dopamine in the synaptic cleft, which causes intense stimulation of the central nervous system and extremely dangerous mental and cardiovascular effects. Another example of synaptic overstimulation is epileptic seizures, in which susceptible individuals experience episodes of hypersynchronization of cortical neurons, leading to convulsions or other involuntary brain attacks. Such excesses can be devastating to individuals. For society, aggression, violence and other forms of excessive behavior are sometimes preventable through gentle communication, withholding the means to harm, or implementing restraining factors.

Persistent synaptic signals can also occur abnormally. An example is chronic neuropathic pain. Long after acute bodily injury has ceased, sensitized central sensory systems may perpetuate the experience of pain, whether at rest or in response to ordinary sensory inputs that formerly were not painful. Similarly, synaptic sensitization is partly responsible for some forms of persistent anxiety such as post-traumatic stress disorder, in which the individual experiences lingering apprehension and autonomic arousal years after an emotionally traumatic event. These disorders cause much suffering. Their experience is often intertwined with personal memory, body image and identity. Touching on these areas in conversation requires the utmost in delicacy and compassion. For society, as for individuals, sensitive issues often relate to remembered historical events that shape cultural identity. Approaching them in dialogue requires the utmost in mutual respect and empathy.

Some types of blindness have been linked to specific molecular synaptic defects.[11],[12] Analogously, some types of societal misconceptions have been linked to misleading communication in biased journalism.[13],[14]

It takes at least two neurons to form a synapse. The neuron does not cogitate alone, nor does the brain reason in isolation. Cortical neurons are richly interconnected through an abundance of synapses. As far as neuroscience has determined, there is no one area in the brain that has access to all the brain knows. Similarly, in society no one group of people has exclusive possession of all knowledge or access to all truth. Solving complex ethical problems requires a broad conversation. Wise decision-makers do not limit their information base to communication drawn from within their own specialty but are receptive to the ideas, experience and perspectives of others from diverse backgrounds. This, too, is a brain-based principle, as neurons learn not only from synaptic inputs from other neurons but also from their connections with all manner of peripheral receptors in touch with the rest of the body and with the external world. These receptors transduce information about light, sound, movement, pain and temperature into the common neuronal language of electrical signals.

The synapse merits admiration as a compact locus of communication among neurons and between neurons and other cells. The synapse also vibrantly displays biological principles of effective information exchange. Some features of the elegant design and disease failures of the synapse are relevant to understanding and improving upon human communication, whether it be habits of explicit or nuanced language, electronic messaging, medical conversations at the bedside, or ethical discourse. In so doing, it is also important to keep in mind that models have limitations. It would be a mistake to reduce the meaning of human communication to what occurs at the nanometer scale of the synapse. Even so, history suggests that humankind still has lessons to learn about harmonious communication. The simple synapse may contain useful pointers.

Amidst a multitude of synapses, few neurons ever play an individual role. Neuroscience has discovered, however, that, in some instances, the voice of even an individual neuron can make a difference.[15] Endowed with so many synapses, one person can make a world of difference.

 

References


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[2] Williams RW and Herrup K. "The control of neuron number." Annu Rev Neurosci 1988;11:423–453.

[3] Tang Y, Nyengaard JR, De Groot DM, Gundersen HJ. "Total regional and global number of synapses in the human brain neocortex." Synapse 2001;41:258–273.

[4] Bruel-Jungerman E, Davis S, Laroche S. "Brain plasticity mechanisms and memory: a party of four." Neuroscientist 2007;13:492–505.

[5] Zhuo M. "A synaptic model for pain: long-term potentiation in the anterior cingulate cortex." Mol Cells 2007;23:259–271.

[6] Watts J and Thomson AM. "Excitatory and inhibitory connections show selectivity in the neocortex." J Physiol 2005;562:89–97.

[7] Wang X-J, Tegnér J, Constantinidis C, Goldman-Rakic PS. "Division of labor among distinct subtypes of inhibitory neurons in a cortical microcircuit of working memory." PNAS 2004;101:1368–1373.

[8] Huang ZJ, Di Cristo G, Ango F. "Development of GABA innervation in cerebral and cerebellar cortices." Nat Rev Neurosci 2007;8:673–686.

[9] Barbas H and Zikopoulos B. "The prefrontal cortex and flexible behavior." Neuroscientist 2007;13:532–545.

[10] Damasio H, Grabowski T, Frank R, et al. "The return of Phineas Gage: clues about the brain from the skull of a famous patient." Science 1994;264:1102–1105.

[11] Kremer H, van Wijk E, Märker T, et al. "Usher syndrome: molecular links of pathogenesis, proteins and pathways." Hum Mol Genet 2006;15:R262–270.

[12] Wycisk KA, Zeitz C, Feil S, et al. "Mutation in the auxiliary calcium-channel subunit CACNA2D4 causes autosomal recessive cone dystrophy." Am J Hum Genet 2006;79:973–977.

[13] Garrett JM and Bird SJ. "Ethical issues in communicating science." Sci Eng Ethics 2000:6:435–442.

[14] Cheshire WP. "Human embryo research and the language of moral uncertainty." Am J Bioeth 2004;4:1–5.

[15] Rancz EA, Ishikawa T, Duguid I, et al. "High-fidelity transmission of sensory information by single cerebellar mossy fibre boutons." Nature 2007;450:1245–1248.

 

Editor's Note: This article originally is developed from the lecture, The Wisdom of the Synapse, delivered on 14 July 2007 at the 14th Annual International Conference on Bioethics: Bioethics Nexus: The Future of Healthcare, Science, and Humanity, Deerfield, USA. This article appeared in Ethics & Medicine: An International Journal of Bioethics 24, no. 2, (2008): 77–81 and is used with permission.

 

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