Perineuronal nets support astrocytic ion and glutamate homeostasis at tripartite synapses

Abstract

Perineuronal nets (PNNs) are dense, negatively charged extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. Synapses can be embedded and stabilized by PNNs believed to prevent synaptic plasticity. We find that in cortical fast-spiking interneurons synaptic terminals localize to perforations in the PNNs, 95% of which contain either excitatory or inhibitory synapses or both. The majority of terminals also colocalize with astrocytic processes expressing Kir4.1 as well as glutamate (Glu) and GABA transporters, hence can be considered tripartite synapses. In the adult brain, degradation of PNNs does not alter axonal terminals but causes expansion of astrocytic coverage of the neuronal somata. However, loss of PNNs impairs astrocytic transmitter and K+ uptake and causes spillage of synaptic Glu into the extrasynaptic space. This data suggests a hitherto unrecognized role of PNNs, to synergize with astrocytes to contain synaptically released signals.

Matrix disequilibrium in Alzheimer’s disease and conditions that increase Alzheimer’s disease risk

“…PNNs also prevent lateral diffusion of GluA receptors (Frischknecht et al, 2009). Moreover, PNNs may help to localize presynaptic glutamate that is released onto PV expressing cells (Tewari et al, 2023). Consistent with these effects, disruption of PNNs has been linked to an increase in pyramidal cell activity at the single cell and population level (Slaker et al, 2015;Lensjø et al, 2017;Bozzelli et al, 2018;Alaiyed et al, 2020).…”

Perineuronal Net Microscopy: From Brain Pathology to Artificial Intelligence

“…Third, it may have a crucial effect on the GABA spillover to neighbouring synapses (Figure 3). Astrocyte current recordings under the ChABC treatment suggest that PNN barriers are required for glutamate and K + uptake by astrocytes and that the ChABC-induced PNN digestion causes the glutamate and K + spillage to the extrasynaptic space [28]. For GABA, the PNN-dependent control of extrasynaptic spillage may also be significant because the GABA concentration around the synaptic cleft is not regulated as tightly as the glutamate concentration via high-affinity uptake [24,159,160].…”

“…As a result, Dityatev and Rusakov proposed the concept of tetrapartite synapse or "synaptic quadriga" [24], highlighting the role of the ECM in synaptic transmission and plasticity. The other three parts of the quadriga, presynapse, postsynapse and astrocytes, have been shown to cross-signal intensely with the surrounding ECM, including the PNN [25][26][27][28]. Therefore, we may expect the ECM to contribute significantly to a range of pathology mechanisms that were previously attributed to neurons and/or glial cells [29].…”

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

“…Apart from metabolic functions, a dysfunctional glutamate homeostasis by astrocytes, with downregulation of the metabotropic glutamate receptor 3 (GRM3) and the excitatory amino acid transporter (SLC1A3) were suggested by our results (padjGRM3 = 0.007411, log2FCGRM3 = -2.369, padjSLC1A3 = 0.09633, log2FCSLC1A3 = -1.744). Also related to glutamate homeostasis and the overall neuronal function, astrocytes additionally showed evidence of upregulation of ECM components (VCAN, NCAN, B3GAT2, HS6ST1, GPC6, HS6ST3), that form perineuronal nets in the brain, maintain glutamate homeostasis 78 and the excitatory/inhibitory signalling balance [48][49][50] and are a possible target of lithium, a mood stabilizer widely used for BD treatment 79 . Given the fact that NCAN expression is increased in astrocytes, and has been identified as a gene associated to the genetic risk for BD 7 we also performed immunohistochemistry (IHC) within the Cg which confirm this upregulation of NCAN in the WM (one-tailed t-test, p = 0.02867, Figure 5I, J).…”