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Neuroscience Breakthroughs Since Graduate School - Part 4: Neurons

Updated: Mar 2

human connectome

The brain uses a sophisticated communication and command-and-control system that monitors and manages interactions between roughly 100 billion neurons, each with 5,000-10,000 synaptic connections, for as many as 500 trillion synapses in adults. Neuroscientists have learned a great deal more about neuronal function since graduate school. The most important findings are that the adult human brain creates new neurons, silent synapses may mediate neuroplasticity in adulthood, the lymphatic system extends to the brain, networks of neurons exhibit mirroring properties, neurons can release more than one neurotransmitter (NT), release NTs outside of a synapse, conduct two-way conversations, modulate NT release and action, talk to the astrocytes that enclose the synapse, and electrically communicate almost instantaneously. Research has expanded our understanding of the roles of astrocytes in regulating neuron growth, function, signaling, information processing, synapse formation and elimination, and brain waves.

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The Chemical Synapse

Neurons communicate through the release of over 200 neurochemicals and ions. Axon terminal buttons release neurochemicals across a 20-50-nm fluid-filled gap between presynaptic and postsynaptic structures called a synaptic cleft and into the extracellular fluid surrounding the neuron (Bear et al., 2020). Chemical synapses produce short-duration (millisecond) and long-duration (seconds to days) changes in the nervous system. Synapse animation without sound © 3Dme Creative Studio/

They are functionally asymmetrical because the presynaptic neuron sends a chemical message and the postsynaptic neuron receives it. They are structurally asymmetrical because the presynaptic element (axon) contains vesicles containing neurotransmitters, and the postsynaptic element (dendrite) doesn’t. Neurotransmitter (NT) release from a terminal button is called exocytosis (Breedlove & Watson, 2023). Chemical synapse graphic © rob9000/

Chemical Synapse

In the graphic below, an axon terminal button releases NTs into the synaptic cleft. Neurotransmitters briefly form covalent bonds with receptors on a dendritic spine and then disengage after they initiate small graded potential changes (e.g., EPSPs or IPSPs) or more diverse, gradual, and long-lived actions (e.g., creating second messengers inside the target neuron). Chemical synapse graphic © nobeastsofierce/

Chemical synapse

Neuroscientists have learned a great deal more about neuron-to-neuron communication since graduate school. The most important findings are that the adult brain creates new neurons, silent synapses may mediate neuroplasticity in adulthood, the lymphatic system extends to the brain, neuronal networks exhibit mirroring properties, and neurons can release more than one NT, release NTs outside of a synapse, conduct two-way conversations, modulate NT release and action, talk to astrocytes that enclose synapses, and electrically communicate almost instantaneously.


Neuroscience has challenged the doctrine that the adult human brain does not create new neurons. There is a consensus that neurogenesis occurs in the hippocampus (Eriksson et al., 1998) and olfactory bulb (Lim & Alvarez-Buylla, 2016). However, neurogenesis outside the hippocampus remains controversial. Animal research has yielded evidence of functionally significant neurogenesis in the amygdala, caudate nucleus and putamen (striatum), cortex, hypothalamus, and substantial nigra (Jurkowski et al., 2020). The neurogenesis graphic © VectorMine/


Silent Synapses

Silent synapses are inactive due to the absence of glutamate AMPA receptors. Researchers studying adult mice discovered these synapses on the ends of threadlike filopodia. The simultaneous firing of two neurons connected by a silent synapse causes missing AMPA receptors to appear on the filopodia cell membrane and remodel it to resemble a dendritic spine (Vardalaki et al., 2022). The next step is to determine whether the adult human brain also contains silent synapses. If it does, they are a potential target for increasing cognitive flexibility in the elderly.

Holly Barker (2022) writing for The Scientist, explained:

The study may explain how the brain is able to learn new things without having to sacrifice existing connections, the researchers say. The ability of the brain to use different synapses 'solves the plasticity versus flexibility dilemma,' says Harnett. If all the brain’s synapses are flexible, then you can’t preserve old information. But if they’re all stable, then it is difficult to learn new things, he says. Instead, the brain employs both: spiny synapses for stability and filopodia for flexibility.
But instead of distinct categories, Harnett’s group are beginning to think about dendritic projections as existing on a continuum, from filopodia on one end to mature spines at the other. 'It is a spectrum of maturity, strength, and plasticity,' says study author Dimitra Vardalaki, a PhD candidate in Harnett’s lab.

The Glymphatic System

The belief of an absence of conventional lymphatic vessels in the CNS contributed to the concept that the brain, in spite of its high metabolic rate, represents an immune privileged region. This idea left questioned how cerebral interstitial fluid is cleared from waste products. It was generally thought that clearance depended on cerebrospinal fluid (CSF), acting as a pseudo-lymphatic system (Natale et al., 2021).

The human brain contains a recently-discovered glymphatic system. This astrocyte-controlled lymphatic system removes cellular debris, proteins, and wastes (Xie et al., 2013). The flushing of toxic substances may protect us from neurological disorders like Alzheimer’s (Breedlove & Watson, 2023).

Mirror Neurons

Researchers discovered primate neurons with motor and visual properties in the premotor cortex. The mirror properties are due to a neuron's connections and not its construction. The cortex graphic © Vasilisa Tsoy/

Premotor area

These mirror neurons fired when primates grasped and manipulated objects, and another primate or human performed the same action (Di Pelligrino et al., 1992; Rizzolatti & Craighero, 2004). Mirroring extends across species, including facial expressions. Mirror neuron graphic © xrender/ 

mirror neurons

Investigators have speculated that the human mirror neuron system (MNS) may mediate empathy, imitation learning, language, social cognition, and theory of mind (Buccino et al., 2006; Rajmohan & Mohandas, 2007; Schmidt et al., 2021). Heyes et al. (2021) summarized the state of our knowledge about the MNS.

For action understanding, multivoxel pattern analysis, patient studies, and brain stimulation suggest that mirror-neuron brain areas contribute to low-level processing of observed actions (e.g., distinguishing types of grip) but not to high-level action interpretation (e.g., inferring actors’ intentions). In the area of speech perception, although it remains unclear whether mirror neurons play a specific, causal role in speech perception, there is compelling evidence for the involvement of the motor system in the discrimination of speech in perceptually noisy conditions. For imitation, there is strong evidence from patient, brain-stimulation, and brain-imaging studies that mirror-neuron brain areas play a causal role in copying of body movement topography. In the area of autism, studies using behavioral and neurological measures have tried and failed to find evidence supporting the 'broken-mirror theory' of autism.

Neurotransmitter Co-Release

Dale's law proposed that a neuron releases only one NT. However, researchers have found increasing evidence of NT co-release (Svensson et al., 2019). A neuron can store different NTs in separate types of vesicles (Hökfelt et al., 2003).

Neurons can also store multiple NTs in the same vesicles (e.g., ATP and glutamate), although they may not release them simultaneously (Merighi et al., 2011; Xia et al., 2009).

Extra-Synaptic Transmission: Think Outside the Cleft

Neurons release NTs outside of classical synapses. These mechanisms include release from terminal buttons into the extracellular space, axonal varicosities, and retrograde transmission.

Volume Transmission

Volume transmission involves NT release and eventual binding to a receptor outside the synaptic cleft (Coggan et al., 2005). Graphic adapted from the American Scientist.

Volume Transmission

Axonal Varicosities

Axons can release NTs into the extracellular space through varicosities (swellings) along their length, analogous to drip irrigation (Breedlove & Watson, 2023).

Most neurons that release norepinephrine do not do so through terminal buttons on the ends of axonal branches. Instead, they usually release them through axonal varicosities, beadlike swellings of the axonal branches (Carlson & Birkett, 2019, pp. 82-83).

Retrograde Transmission

In retrograde transmission, a presynaptic neuron sends a chemical message to the postsynaptic neuron. In response, the postsynaptic neuron synthesizes and distributes an endocannabinoid (e.g., anandamide) or gas (e.g., nitrous oxide) to the presynaptic neuron and its immediate active neighbors. Neurons synthesize these NTs on demand since they cannot be contained by vesicles.

. . . this gaseous signal has a range of influence that extends well beyond the cell of origin, diffusing a few tens of micrometers from its site of production before it is degraded. This property makes NO a potentially useful agent for coordinating the activities of multiple cells in a localized region and may mediate certain forms of synaptic plasticity that spread within small networks of neurons (Purves, 2017, pp. 142-143).

Retrograde NTs can bind to membrane-bound receptors or diffuse into the target cell, initiating second messenger production to adjust synaptic efficiency in learning and memory (Breedlove & Watson, 2023).


Modulation is analogous to a volume control knob instead of an on/off switch on a stereo preamplifier; analog instead of digital.

Simaudio preamplifier

We will consider two of countless modulation mechanisms: modulation of NT release and modulation of NT action at its receptor.

Neurotransmitter Release Modulation

Axons can influence the amount of NT released when an action potential arrives at an axon terminal through axoaxonic synapses (junctions between two axons).

Axoaxonic synapses do not affect the generation of an action potential, only the amount of NT release. In presynaptic facilitation, a neuron increases the presynaptic neuron's NT release by delivering a NT that increases calcium ion entry into its terminal button. In presynaptic inhibition, a neuron decreases NT release by reducing calcium ion entry. These modulatory effects are confined to a single synapse (Breedlove & Watson, 2023).

Autoreceptors Modulate Neurotransmitter Release

Autoreceptors are metabotropic receptors on the presynaptic membrane (see step 7). When NTs released into the synaptic cleft bind to autoreceptors, this hyperpolarizes the axon terminal button so it will release less NT when the next action potential arrives.

Neuromodulators Adjust Neurotransmitter Action

Receptors contain binding sites for a NT like GABA and drugs like alcohol. When alcohol binds to its allosteric site, it strengthens GABA's covalent bond with its orthosteric site, causing greater chloride entry into the neuron, increasing its hyperpolarization. Ingesting multiple CNS depressants (e.g., alcohol and barbiturates) can yield dangerous additive effects, amplifying GABA's action to a level that can depress or stop breathing.


Astrocytes are star-shaped glial cells in the central nervous system (i.e., brain and spinal cord) that perform vital functions. Astrocyte endfeet form junctions with capillaries comprising part of the protective blood-brain barrier. They regulate blood flow to the neuron, delivering stored glucose during peak metabolic demand (Schummers et al., 2008). Astrocyte graphic © Kateryna Kon/


Astrocytes enclose synapses, determine where synapses can form by releasing specialized molecules, regulate synapse maturation, bidirectionally communicate with synapses, prune surplus synapses, help neurons regulate brain microcirculation, and eavesdrop on nearby synapse activity (Breedlove & Watson, 2023; Parri & Crunelli, 2003: Shan et al., 2021).

Astrocytes transport amino acid NTs (e.g., GABA and glutamate) from the synaptic cleft.

Astrocytes are theorized to participate in gliotransmission between neurons and each other (Eroglu & Barres, 2010; Perea et al., 2009). However, gliotransmission remains controversial.

. . . the physiological role of gliotransmission is highly debatable . . . as gliotransmitter release has been reliably demonstrated only in vitro in cultures and brain slice experiments that are often accompanied by manipulations (e.g., high frequency stimulation) which can affect astrocytic channels or receptors leading to impaired signaling cascades. This experimental design imposes questions about the existence of gliotransmission . . . and whether it plays a physiological role in the brain . . . (Buskila et al., 2019).

The presynaptic and postsynaptic neurons and astrocytes comprise a tripartite synapse.

An essential role of astrocytes is regulating the chemical content of this extracellular space. For example, astrocytes envelop synaptic junctions in the brain, thereby restricting the spread of neurotransmitter molecules that have been released. Astrocytes also have special proteins in their membranes that actively remove many neurotransmitters from the synaptic cleft. A recent and unexpected discovery is that astrocytic membranes also possess neurotransmitter receptors that, like the receptors on neurons, can trigger electrical and biochemical events inside the glial cell (Bear et al., 2020, p. 49).

Astrocyte glutamate release may be essential for hippocampal long-term depression (LTD), a long-lasting reduction in transmission strength, and long-term memory modulation (Navarrete et al., 2019). Astrocyte calcium and brain-derived neurotrophic factor (BDNF) release appear critical for late-phase hippocampal long-term potentiation (LTP), a long-lasting increase in transmission strength, and long-term memory regulation (Liu et al., 2021).

Astrocytes communicate with each other through gap junctions (Bennett et al., 2003).

Finally, astrocytes may contribute to brain waves by regulating synapses via gap junctions and calcium signaling.

These capabilities allow astrocytes to regulate neuronal excitability via glutamate uptake, gliotransmission and tight control of the extracellular K+ levels via a process termed K+ clearance. Spatio-temporal synchrony of activity across neuronal and astrocytic networks, both locally and distributed across cortical regions, underpins brain states and thereby behavioral states, and it is becoming apparent that astrocytes play an important role in the development and maintenance of neural activity underlying these complex behavioral states (Buskila et al., 2019).

Electrical Synapses

Electrical synapses communicate information across gap junctions between adjacent membranes using ions. Gap junctions are narrow spaces between two cells bridged by connexons (protein channels) that allow ions near-instantaneous travel. Gap junction illustration © VectorMine/

Gap junction

Electrical synapses are generally symmetrical. Ions flow across a 3-nm gap junction into the more negatively charged neuron as long as the gap junction remains open. This means that whether neurons are presynaptic or postsynaptic depends on their respective charges. When two neurons are electrically coupled, an action potential in one induces a postsynaptic potential (PSP) in the paired neuron.

Transmission across electrical synapses is nearly instantaneous, compared with the 10-ms or longer delay in chemical synapses. The rapid information transmission that characterizes electrical synapses enables large circuits of neurons to synchronize their activity and simultaneously fire.

Studies in recent years have revealed that electrical synapses are common in every part of the mammalian CNS. When two neurons are electrically coupled, an action potential in the presynaptic neuron causes a small amount of ionic current to flow across the gap junction channels into the other neuron. This current causes an electrically mediated postsynaptic potential (PSP) in the second neuron. Note that, because most electrical synapses are bidirectional, when that second neuron generates an action potential, it will in turn induce a PSP in the first neuron (Bear et al., 2020, p. 113).

Neurons that secrete hormones use electrical synapses to release their chemical messengers simultaneously. Neonatal brains may use gap junctions to activate many neurons at once. Image of long, fibrous astrocyte processes using Golgi's silver chromate technique © Jose Luis Calvo/


Gap junctions may be a preliminary step toward developing chemical synapses between these neurons, eventually replacing their electrical synapses. Prenatally and postnatally, gap junctions enable nearby neurons to coordinate their development by sharing electrical and chemical communications. Adult synapses can be electrical and chemical (Bear et al., 2020; Breedlove & Watson, 2023).


The most important findings are that the adult human brain creates new neurons, silent synapses may mediate neuroplasticity in adulthood, the lymphatic system extends to the brain, networks of neurons exhibit mirroring properties, neurons can release more than one neurotransmitter (NT), release NTs outside of a synapse, conduct two-way conversations, modulate NT release and action, talk to the astrocytes that enclose the synapse, and electrically communicate almost instantaneously. Research has expanded our understanding of the roles of astrocytes in regulating neuron growth, function, signaling, information processing, synapse formation and elimination, and brain waves.


Take a five-question quiz on Quiz Maker to assess your mastery.

Questions Worth Asking

Why don't action potentials travel in both directions along an axon?

After an axon segment is depolarized, it enters an absolute refractory period in which it cannot fire, regardless of stimulus intensity.

Why don't dendrites typically initiate action potentials?

Most dendrites lack the voltage-gated sodium channels required for action potentials. Illustration 180855817 © Juan Gaertner |

sodium channel

Artist note. Na+ channels are composed of a large alpha subunit and one or more regulatory beta subunits dark blue. They generate and propagate action potentials in neurons and muscle.


absolute refractory period: when a neuron cannot initiate a second action potential regardless of stimulus intensity.

active zone: presynaptic terminal button region, including the presynaptic membrane, specialized for neurotransmitter release.

allosteric site: modulatory binding site on a NT's receptor complex.

amino acid: protein building blocks containing both a carboxyl (—COOH) and an amino (—NH2) group. anandamide: a fatty acid neurotransmitter derived from arachidonic acid.

astrocyte endfeet: specialized astrocyte processes that comprise part of the blood-brain barrier.

axon terminal button: an axon's bulblike termination specialized for neurotransmitter release.

axonal varicosities: swellings along an axon's length through which neurotransmitters are released.

blood-brain barrier: a semipermeable barrier of capillary endothelial cells and astrocyte endfeet that regulates large and small molecule entry into the brain, and protects against circulating pathogens and toxins.

brain-derived neurotrophic factor (BDNF): a protein belonging to the neurotrophin growth factor family that is involved in neuron growth and repair. BDNF is a neuromodulator that mediates neuronal plasticity essential to learning and memory.

co-release: the release of multiple neurotransmitters by the same neuron (e.g., GABA and glutamate). co-storage: storing multiple neurotransmitters in the same vesicles (e.g., GABA and glutamate).

connexon: a protein comprised of six connexins that forms a gap junction between adjacent cell cytoplasm.

dendritic spine: a small protrusion from a dendritic shaft that increases the surface area for expressing receptors.

depolarization: a membrane potential shift to a less negative value.

electrical synapse: a gap junction between neurons for the rapid and often bidirectional movement of ions and small molecules. excitatory amino acid transporter (EAAT): transporters in CNS glial cells and neurons that remove glutamate from the synaptic cleft.

gliotransmission: calcium-dependent astrocyte neurotransmitter release.

glymphatic system: an astrocyte-controlled lymphatic system that removes cellular debris, proteins, and wastes from the brain.

hyperpolarization: a negative membrane potential shift. long-term depression: a weakening of synaptic connections for hours or longer caused by low-frequency stimulation.

long-term potentiation: a strengthening of synaptic connections for hours or longer caused by high-frequency stimulation.

mirror neuron: a neuron activated when performing a movement and when observing another person making the exact movement.

monoamine: a biogenic amine containing a single amino group, including dopamine, epinephrine, norepinephrine, and serotonin. orthosteric site: a NT's binding site.

peptide: a short amino acid chain linked by peptide bonds (e.g., opioid peptides, oxytocin, substance P).

premotor cortex: nonprimary motor cortex anterior to the primary motor cortex. presynaptic facilitation: a neuron increases the presynaptic neuron's NT release at an axoaxonic synapse by delivering a NT that increases calcium ion entry into its terminal button, depolarizing it.

presynaptic inhibition: a neuron decreases the presynaptic neuron's NT release at an axoaxonic synapse by delivering a NT that decreases calcium ion entry into its terminal button, hyperpolarizing it. retrograde transmission: a signaling process in which the postsynaptic neuron dendrite or cell body synthesizes and distributes an endocannabinoid (e.g., anandamide) or gas (e.g., nitrous oxide) to the presynaptic neuron and its immediate active neighbors.

synaptic cleft: a 20-50-nm fluid-filled gap between presynaptic and postsynaptic structures.

voltage-gated sodium channel: a membrane-bound sodium ion channel required for action potentials that opens and closes in response to the membrane potential.

volume transmission: widespread neurotransmitter distribution via the extracellular fluid and cerebrospinal fluid.


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