Perineuronal Nets, aka Golgi vs Cajal (Round 2)


I'm going to tell you a story about the perineuronal net. The what, now? I hear (some of) you cry.

If neurons and glia are the plants of our brains, the extracellular matrix is the trellis upon which those plants grow and intertwine. The peri neuronal net is a specialized portion of the extracellular matrix, surrounding (primarily) the soma and proximal dendrites of parvalbumin positive interneurons. The mesh-like structure of the perineuronal net, holes accommodating synaptic contacts onto the embedded neurons, appears critical for forming and stabilizing synapses.

The appearance of the perineuronal net coincides with the closing of critical periods; enzymatic breakdown of the perineuronal net can reinstate ocular dominance plasticity in adult animals. (This flavor of plasticity can usually only be triggered in juveniles.) Also, degrading the perineuronal net allows extinction training to fully eliminate fear conditioning in adult animals, a feat usually only possible in juvenile animals (adults respond to extinction training with only a temporary inhibition of fear responses) (1). Thus, many independent studies implicate the perineuronal net as a negative regulator of plasticity. The net stabilizes synapses, preventing unwanted change within established brain circuits.

Interestingly, the perineuronal net appears damaged following status epilepticus, a prolonged seizure event that commonly triggers epileptogenesis, and is followed by axonal sprouting and enhanced synapse numbers within the hippocampus (1). The loss of the perineuronal net may establish a permissive environment for the widespread synaptic reorganization that occurs during temporal lobe epileptogenesis.

So to summarize: the perineuronal net, and its parent structure, the extracellular matrix, may be important for establishing the synaptic stability that maintains the delicate interconnections of the nervous system.

So, the story.

Epic Science Battles of History: The Aftermath

The first thing you need to understand is that it took until the 1980s for the perineuronal net to be accepted as an interesting, important, and in fact existing, structure. Despite the first published description occurring almost 100 years earlier, in 1898.

Why the long delay?

Turns out the perineuronal net was a victim of the fallout of probably the most famous science fight in neuroscience.

That's right, this story involves Santiago Ramon y Cajal and Camillo Golgi.

Cajal and Golgi are, of course, well known for their decades long disagreement over whether the nervous system is a continuous network (the reticular theory, Golgi's view), or comprised of distinct cells (neuronal doctrine, the correct answer). The controversy between the reticularists and the proponents of the neuronal doctrine would have been ongoing in 1898, when Golgi presented his observations of the perineuronal net, "a continuous envelop that enwraps the body of all the nerve cells extending to the protoplasmic prolongements up to second and third order arborizations" (2). Contemporaries of Golgi followed up on his initial observations (most notably: Donaggio, who described the filamentous pattern within the net; Bethe, who differentiated between perineuronal nets and the more diffuse extracellular matrix; and Held, who proposed shared components, and a glial origin for the perineuronal and diffuse nets) (2).

But this initial period of study came to an abrupt halt by the entrance of Ramon y Cajal onto the scene.

Cajal was of the opinion that the perineuronal nets observed by Golgi (and everyone else), were nothing more than a coagulation artifact produced during the staining process that bears Golgi's name.

According to Carlo Besta (neurologist and psychiatrist), Cajal's victory on the subject of the neuronal doctrine made his word automatically superior that of Golgi, Held, Bethe and Donaggio. "It has been sufficient that Cajal claimed that [perineuronal] and diffuse nets were an artifact ... and most of the scientific world took no further interest in the matter" (3).

Although a few individuals continued to investigate the perineuronal net (including G.B. Belloni, who observed structural changes in both perineuronal and diffuse nets in humans suffering from dementia, gliosis and psychiatric diseases), in general, research stagnated until the 1980s, when the advent of better staining techniques made it possible to reveal perineuronal nets as real structures, and not mere artifacts of an imperfect staining technique (2).

The modern study of the perineuronal nets is still in its infancy (as is, for that matter, all of neuroscience), but as the previous section attests, several studies have hinted at a role in restricting plasticity, maintaining a stabilized environment for neuronal (and glial) function.

Which brings me to the final note of this post, which also happens to be the trigger of my recent readings into the history of the perineuronal net.

A Modern "Prophecy"

Back in June, a lab mate of mine passed around a PNAS article with a provocative title, and an attention-grabbing author.

The article? "Very long-term memories may be stored in the pattern of holes in the perineuronal net." By (Nobel Prize Winner) Roger Tsien.

So, I'm not going to do a full analysis of Tsien's article, which reads more like an RO1 than anything else. His basic thesis is based on the assumption that long-term memory storage within the human brain necessarily involves a long-term molecular substrate. Tsien identifies the molecules that make up the perineuronal net as likely candidates for the molecules that encode our long-term memories. He steps beyond the more comment supposition that the perineuronal net is a permissive structure for synaptic stability, claiming that "very long-term memories are stored in the pattern and size of holes in the PNN [perineuronal net]…" (4). Lest we confuse his proposal with the more common understanding of the function of the perineuronal net, Tsien writes: "reviews on the PNN propose permissive, supportive roles… analogous to the importance of insulation on the wiring inside a computer: essential for function but not where bytes are dynamically stored." (4) Tsien maintains that the perineuronal net is the storage device for long-term memories, the location where "bytes are dynamically stored."

Tsien's hypothesis, which he compares to Watson and Crick's theory of DNA, is severely lacking in experimental evidence. Thus the PNAS article, in which Tsien describes experiments he believes will test his hypothesis. Having read the article abstract-to-bibliography multiple times, I remain unconvinced that the proposed experiments would be sufficient to support Tsien's theory. Will the experiments prove insightful? Does the perineuronal net directly encode bytes of long-term memory? We may have to wait another 100 years to find these answers, as Tsien seems to have no plans to actually conduct the experiments he proposes. Instead, he hopes that other scientists will use his PNAS paper as a roadmap for future experiments. Extending his Watson and Crick metaphor, he calls for the Rosalind Franklin's of the world to supply him with the experimental data his hypothesis demands; "Perhaps, in a few years, at least one prophecy can be vindicated" (4). As someone who has, uh, heard of Franklin, I wonder if Tsien realizes what a raw deal his is proposing for his fellow scientists.


  1. McRae and Porter (2012). The perineuronal net component of the extracellular matrix in plasticity and epilepsy. Neurochemistry International 61: 963-972. Link
  2. Vitellaro-Zuccarello, De Biasi, Spreafico (1998). One hundred years of Golgi's "perineuronal net": history of a denied structure. Ital J Neurol Sci 19:249-253. Link
  3. Besta C (1928) Dati sul reticolo periferico della cellula nervosa, sulla rete interstiziale diffusa e sulla loro probabile derivazione da particolari elementi cellulari. Boll Soc It Biol Sper 3:966-973
  4. Tsien (2013). Very-long term memories may be stored in the pattern of holes in the perineuronal net. PNAS 110(30): 12456-12461. Link


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Astra Bryant

Astra Bryant is a graduate of the Stanford Neuroscience PhD program in the labs of Drs. Eric Knudsen and John Huguenard. She used in vitro slice electrophysiology to study the cellular and synaptic mechanisms linking cholinergic signaling and gamma oscillations – two processes critical for the control of gaze and attention, which are disrupted in many psychiatric disorders. She is a senior editor and the webmaster of the NeuWrite West Neuroblog