Perineuronal nets: the extracellular matrix in memory

By Jhonata Lam

Cells often sit in an environment consisting of an agglomeration of proteins and sugars termed the extracellular matrix. This can be fine-tuned to suit certain needs of specialised cell types in the body. Particularly, the human central nervous system, i.e. the brain and spinal cord, possesses a highly specialised extracellular matrix, which is given the moniker perineuronal net (PNN). Originally, its existence was inferred from experiments back in the 1800s carried out by the esteemed pathologist Camillo Golgi. Golgi found that a network-like structure enveloped certain parts of neurons, namely the dendrites and soma.^1,2 With time, many have elaborated on the function of PNNs in the maintenance of synapses, and plasticity.³ Such findings inevitably raise interesting questions on how perineuronal nets influence memory throughout normal human lifespan, and whether the medical field could adjust this environment to promote physical recuperation in the case of pathological insult. 

Structurally, PNNs share several common components, and these include molecules known as chondroitin sulfate proteoglycans (CSPs), hyaluronan, link proteins, and tenascin.¹ Many CSPs link to a single hyaluronan molecule through the link protein,⁴ and hyaluronan itself is attached to neuronal surfaces via the enzyme that produces it, hyaluronan synthase.⁵ Also worthy of note is that some of these molecules are highly negatively charged at physiological pH, such as the sulfate groups of CSPs. This thereby imparts an overall negative charge on the entire network, which is integral for neuronal communication.  

Intriguingly, it has been suggested that PNNs play a role in the maintenance of memory. For instance, there are some studies finding that reducing PNN components, like degrading hyaluronan with the enzyme hyaluronidase⁶ or RNA-mediated knockdown of another component brevican,⁷ decreased the mobility of memory-associated AMPA receptor proteins on neuron surfaces. AMPA receptors (a receptor for the brain’s major excitatory neurotransmitter glutamate) have been well studied to be involved in long-term potentiation (LTP), a process associated with memory.⁸ Mechanistically, AMPA receptors are recruited to a portion of neuronal surface in which NMDA receptors (another glutamate receptor type) are activated.⁹ Their function would be to increase the response when that part of the neuron encounters glutamate, thereby decreasing the threshold for neuronal stimulation, a process vital in learning on a cellular level. Therefore, immobilising AMPA receptors serves to establish these regions, as well as prevent these regions from losing this specialisation by AMPA receptors moving away from the defined space.  

Furthermore, the degree of learning is different between adults and young organisms – and appears to be modulated by PNNs. PNNs regulate the critical period, that is, a period wherein the organism has the greatest synaptic plasticity, i.e. the greatest potential for changes in neuronal connections, throughout its lifetime. An intriguing example arises from the study of fear conditioning. Generally speaking, fears acquired early in life are tenacious and persist into adulthood. Experiments utilising a brain region known as the amygdala sheds light on the molecular basis of such an observation. Researchers injected a CSP-degrading enzyme chondroitinase ABC to this brain region and witnessed a loss of previously acquired fear in mice.¹⁰  Hence, the PNN contributes to the stable conversion of short term memory into long term memory, which other studies have also corroborated.¹¹ 

In clinical deficiencies of memory, therefore, PNN alteration could serve as a therapeutic intervention to combat recall impairments, such as Alzheimer’s disease. Alzheimer’s disease, the most common neurodegenerative disorder whose risk increases with age, is caused by the abnormal accumulation of a fragment of a protein called amyloid-β. A common symptom associated with disease progression in this case is memory loss, which researchers have sought to attenuate via targeting PNNs. Végh et al¹² began by ascertaining the proteins that had higher levels in Alzheimer’s disease mice models specifically in the hippocampus, a brain region associated with memory. Subsequently it was found that proteins of the PNN were greatly upregulated, meaning the functions of this network could be enhanced in the disease. This might suggest synaptic plasticity would be restricted, and thus could provide a molecular basis for memory impairments seen in Alzheimer’s disease. Taking this further, by injecting the CSP-degrading enzyme chondroitinase ABC to downregulate PNNs, the researchers found that impairments in fear conditioning (i.e. a proxy for learning) as well as LTP were mitigated.  

In other cases, PNNs have been associated with well-known psychological disorders like schizophrenia and bipolar disorder.¹³ A study examining the postmortem brains of individuals suffering from schizophrenia and bipolar disorder throughout their lifetime, for example, found that there is reduced size of parvalbumin-containing neurons in a part of the brain called the thalamic reticular nucleus.¹⁴ Parvalbumin-containing neurons are known to have a high degree of PNNs.^1,2,15 The authors allude that through reducing numbers of these neurons, it may affect sufferers by disrupting attention, emotions and sleep – symptoms of which are demonstrated in these disorders – showing the PNN to have profound effects in the pathology of psychological disorders. 

Overall, PNNs appear to be critical elements in the formation and maintenance of memory. Attempting to understand specific molecules of the PNN may reveal additional roles of these networks and elucidate how it works, which may guide future therapeutic interventions in diseases like Alzheimer’s.  Targeting PNNs in neurodegenerative disease patients, may recover of recall and ameliorate quality of life, adding credence to studying this exceptional aspect of the brain. 

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