Perineuronal net

Perineuronal nets (PNNs) are specialized extracellular matrix structures responsible for synaptic stabilization in the adult brain. PNNs are found around certain neuron cell bodies and proximal neurites in the central nervous system. PNNs play a critical role in the closure of the childhood critical period, and their digestion can cause restored critical period-like synaptic plasticity in the adult brain. They are largely negatively charged and composed of chondroitin sulfate proteoglycans, molecules that play a key role in development and plasticity during postnatal development and in the adult. Perineuronal nets (PNNs) are specialized extracellular matrix structures responsible for synaptic stabilization in the adult brain. PNNs are found around certain neuron cell bodies and proximal neurites in the central nervous system. PNNs play a critical role in the closure of the childhood critical period, and their digestion can cause restored critical period-like synaptic plasticity in the adult brain. They are largely negatively charged and composed of chondroitin sulfate proteoglycans, molecules that play a key role in development and plasticity during postnatal development and in the adult. PNNs appear to be mainly present in the cortex, hippocampus, thalamus, brainstem, and the spinal cord. Studies of the rat brain have shown that the cortex contains high numbers of PNNs in the motor and primary sensory areas and relatively fewer in the association and limbic cortices. In the cortex, PNNs are associated mostly with inhibitory interneurons and are thought to be responsible for maintaining the excitatory/inhibitory balance in the adult brain. The existence of PNNs has been inferred by Golgi, Lugaro, Donaggio, Martinotti, Ramón y Cajal and Meyer. However, Ramón y Cajal credits Golgi with the discovery of PNNs because he was the first to draw attention to them and gave the first precise description in 1893. Moreover, Golgi brought interest to the subject due to his opinion that the PNN was not a neuronal structure but rather a 'kind of corset of neurokeratin which impeded the spread of current from cell to cell'. Despite debating the topic, Ramón y Cajal claimed that the perineuronal net was simply a staining artifact derived from the coagulation of extracellular fluids. Due to his influential opinion at the time, interest in the topic subsided. Interest arose in the 1960s when several authors drew attention to the presence of periodic-acid-Schiff-positive (PAS-positive) material surrounding nerve cells. This PAS-positive material was suspected of being composed of negatively charged substances, such as chondroitin sulfate proteoglycans (CSPGs). However, the authors clung to the idea that the material was intricately connected to the blood–brain barrier and failed to see the similarities it had with the perineuronal net described by Golgi. Interest only rose again in the past few decades when it was discovered that PNNs constitute markers for physiologically mature neurons. PNNs are composed of a condensed matrix of chondroitin sulfate proteoglycans, molecules that consist of a core protein and a glycosaminoglycan (GAG) chain. The CS-GAG chains associated with PNNs differs from those found floating in the extra-cellular matrix in a noncondensed form. PNNs are composed of brevican, neurocan, versican, aggrecan, phosphacan, hyaluronan, tenascin-R and various link proteins. The CSPGs aggrecan, versican, neurocan, brevican, and phosphacan are bound to hyaluronan. Many of the components of PNNs are also expressed other forms of ECM in the brain. Aggrecan is selectively expressed in PNNs and is essential for the construction and maintenance of PNNs. PNNs found in both the brain and the spinal cord have the same composition. Chondroitinase ABC (ChABC), a bacterial enzyme routinely used to digest CSPGs, works by catalyzing the removal of the CS-GAG chains of CSPGs, thus it is not selective to PNNs. Mutant mice deficient in tenascin-R or link protein have attenuated PNNs, In the cortex and other subcortical areas, PNNs preferentially surround GABAergic interneurons containing the calcium-binding protein parvalbumin. The onset of the critical period corresponds closely to the emergence of parvalbumin-positive cells. Parvalbumin-positive cells synapse onto α1-subunit-containing GABAA receptors. The α1-subunit-containing GABAA receptors have been shown to be the only GABAA receptors that drive cortical plasticity. For this reason, PNNs were first thought to have a strong role in the closure of the critical period. A fine regulation of axonal and dendritic growth is required in the adult CNS to preserve important connections while still allowing for structural plasticity. This function has been recognized to be mediated by several myelin-associated proteins and CSPGs. In order to assess the physiological role of PNNs in the undamaged CNS, ChABC was injected in the healthy cerebellum of adult rats. In the site of ChABC injections, there was profuse outgrowth of the terminal branches of Purkinje cell neurons. However, myelinated axon segments were not affected and remained normal. Purkinje axon sprouting was first evident four days after the degradation of CSPGs. Within 42 days, the expression of CSPGs gradually recovered, at which point axon outgrowth regressed, indicating that there was no significant formation of stable synaptic contacts. While CSPGs are very important in neuroprotection, this indicates that CSPGs may not be the only molecules important for the preservation of anatomical plasticity. Cell surface proteins, including neurotransmitter receptors, are highly mobile in the plasma membrane due to lateral diffusion. Fast movements of AMPA-type glutamate receptors (AMPARs) are involved in the modulation of synaptic transmission. As a receptor is used, it becomes desensitized and unable to operate efficiently for a short period of time. Diffusion of the desensitized receptor for the exchange of a naive functional one increases synaptic fidelity during fast repetitive stimulation. PNNs compartmentalize the neuronal surface and act as lateral diffusion barriers for AMPARs, limiting synaptic exchange. This may be part of the reason that synaptic plasticity is limited once PNNs become upregulated. Most of the parvalbumin-positive neurons surrounded by PNNs also contain the potassium channel Kv3.1b subunit. These specific cells have been identified as fast-spiking cells. These neurons have a low input resistance of the cell membrane, a high resting membrane potential, a short duration of both action potentials and the refractory period, a high firing frequency, and an almost constant amplitude of their action potentials. It appears that both Kv3.1 channels and PNNs are both required for the fast-spiking behavior of these neurons. These potassium channels are important because outward potassium currents are responsible for the repolarization of the cell membrane during an action potential. It has been shown that Kv3.1 currents allow a neuron to follow a high frequency stimulation and/or to generate high firing rates without spike adaption, characteristics that fit well with fast-spiking cells. This characteristic of the cells is important as blockade of the Kv3.1b channel has been shown to slow the rate of ocular dominance plasticity.