Perineuronal Nets: Subtle Structures with Large Implications

Abstract

Perineuronal nets (PNNs) are specialized structures of the extracellular matrix that surround the soma and proximal dendrites of certain neurons in the central nervous system, particularly parvalbumin-expressing interneurons. Their appearance overlaps the maturation of neuronal circuits and the closure of critical periods in different regions of the brain, setting their connectivity and abruptly reducing their plasticity. As a consequence, the digestion of PNNs, as well as the removal or manipulation of their components, leads to a boost in this plasticity and can play a key role in the functional recovery from different insults and in the etiopathology of certain neurologic and psychiatric disorders. Here we review the structure, composition, and distribution of PNNs and their variation throughout the evolutive scale. We also discuss methodological approaches to study these structures. The function of PNNs during neurodevelopment and adulthood is discussed, as well as the influence of intrinsic and extrinsic factors on these specialized regions of the extracellular matrix. Finally, we review current data on alterations in PNNs described in diseases of the central nervous system (CNS), focusing on psychiatric disorders. Together, all the data available point to the PNNs as a promising target to understand the physiology and pathologic conditions of the CNS.

Daily membrane capacitance changes in mouse neurons

“…Membrane surface (and thus capacitance) changes also happen in the neocortex during synaptic remodeling following daily light/dark patterns; however, those changes are small (Jasinska et al 2019). Membrane capacitance also varies due to wrapping of cells by tight apposition of other membrane layers such as those from Schwann cells and oligodendrocytes during myelination, or the formation of extracellular PNNs around PV + interneurons (Carceller et al 2022). Interestingly, we observe daily capacitance changes only in pyramidal neurons, which are not surrounded by PNNs in the cortex (Carceller et al 2022; Tewari et al 2018).…”

“…Membrane capacitance also varies due to wrapping of cells by tight apposition of other membrane layers such as those from Schwann cells and oligodendrocytes during myelination, or the formation of extracellular PNNs around PV + interneurons (Carceller et al 2022). Interestingly, we observe daily capacitance changes only in pyramidal neurons, which are not surrounded by PNNs in the cortex (Carceller et al 2022; Tewari et al 2018). PNNs are known to change their expression in a circadian manner (Pantazopoulos et al 2020), and given their tight apposition on the membrane of certain neurons, influence membrane capacitance (Tewari et al 2018).…”

A glial perspective on the extracellular matrix and perineuronal net remodeling in the central nervous system

“…Historically, PNNs have been the most intriguing yet enigmatic ECM structures. PNNs are widely expressed in several brain regions including the cerebral cortex, amygdala, striatum, and hippocampus ( Morikawa et al, 2017 ; van’t Spijker and Kwok, 2017 ; Ulbrich et al, 2021 ) as well as in the spinal cord ( Irvine and Kwok, 2018 ) of rodents and humans ( Chaunsali et al, 2021 ; Carceller et al, 2022 ). PNNs are predominantly present on the fast-spiking PV interneurons; however, a small population of other inhibitory and excitatory neurons in brain and spinal cord express PNNs ( Irvine and Kwok, 2018 ; Chaunsali et al, 2021 ).…”

“…Despite being a multimolecular assembly, WFA-labeled PNNs remain minimally distorted in the absence of single or multiple PNN components including HA ( Arranz et al, 2014 ), neurocan ( Zhou et al, 2001 ), brevican ( Brakebusch et al, 2002 ), Tn-C ( Irintchev et al, 2005 ; Gottschling et al, 2019 ), Tn-R ( Brückner et al, 2000 ; Gottschling et al, 2019 ), and link proteins ( Carulli et al, 2010 ). However, as the one indispensable component of the PNN, aggrecan deficiency leads to the absence of PNNs ( Giamanco et al, 2010 ; Rowlands et al, 2018 ) (See review Carceller et al, 2022 ).…”

“…Normally, the homeostatic states of ECM and PNNs are maintained by a constitutive expression of ECM and proteases by neurons and astrocytes, as well as clearance by microglia. However, as seen in several recent studies on epilepsy, Alzheimer’s disease (AD), Huntington’s disease (HD), neuropathic pain, etc., dysfunctional microglia leads to abnormal clearance or accumulation of the ECM and PNNs contributing to the pathology ( Tewari et al, 2018 ; Patel et al, 2019 ; Crapser et al, 2020b , 2021 ; Chaunsali et al, 2021 ; Carceller et al, 2022 ; Tansley et al, 2022 ).…”