Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses

Abstract

The synaptic transmission in the mammalian brain is not limited to the interplay between the pre- and the postsynapse of neurons, but involves also astrocytes as well as extracellular matrix (ECM) molecules. Glycoproteins, proteoglycans and hyaluronic acid of the ECM pervade the pericellular environment and condense to special superstructures termed perineuronal nets (PNN) that surround a subpopulation of CNS neurons. The present study focuses on the analysis of PNNs in a quadruple knockout mouse deficient for the ECM molecules tenascin-C (TnC), tenascin-R (TnR), neurocan and brevican. Here, we analysed the proportion of excitatory and inhibitory synapses and performed electrophysiological recordings of the spontaneous neuronal network activity of hippocampal neurons in vitro. While we found an increase in the number of excitatory synaptic molecules in the quadruple knockout cultures, the number of inhibitory synaptic molecules was significantly reduced. This observation was complemented with an enhancement of the neuronal network activity level. The in vivo analysis of PNNs in the hippocampus of the quadruple knockout mouse revealed a reduction of PNN size and complexity in the CA2 region. In addition, a microarray analysis of the postnatal day (P) 21 hippocampus was performed unravelling an altered gene expression in the quadruple knockout hippocampus.

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

“…For instance, synaptic loss is a key feature of AD pathogenesis mediated, at least in part, by microglia [ 13 , 79 ]. This may be due in part to the degradation of the PNNs in which synapses are embedded, as the genetic ablation of one or more PNN structural components and consequent loss of neuronal PNN integrity can induce the loss of synapses [ 28 , 80 ] and impaired synaptic colocalization/expression of neurotransmitter receptor subunits [29] , potentially manifesting as deficits in synaptic plasticity (e.g. LTP) [81] , [82] , [83] .…”

“…Although enhanced plasticity and learning is observed following experimental PNN ablation [ 23 , 24 ], newly formed memory traces can interfere with the fidelity and recall of previously learned information [20] , as evident by impaired reconsolidation and recall of remote memories following PNN ablation [ 25 , 26 ]. Furthermore, the structural modification of PNNs alters synaptic transmission [27] , synapse number [28] , and the ion channel/neurotransmitter receptor composition of synapses [29] , and thus may be related to the dysfunctional interneuron activity mediating cognitive impairments in AD [ 30 , 31 ].…”

Extracellular matrix supports excitation-inhibition balance in neuronal networks by stabilizing inhibitory synapses

“…On neurons devoid of PNNs, a less dense ECM layer may potentially play a similar role. An increased ratio of excitatory to inhibitory synapses has recently been shown in the hippocampus of mice exhibiting simultaneous knockout of several ECM proteins and glycoproteins as a consequence of disturbed PNN formation (Gottschling et al, 2019).…”

New Insights into ADAMTS Metalloproteases in the Central Nervous System

“…However, the simultaneous absence of brevican and neurocan facilitates the growth of a subpopulation of sensory fibers in the spinal cord dorsal root entry zone (following rhizotomy). A recent study by Gottschling et al [46] revealed new findings about the roles of brevican and neurocan in the CNS and their functional relationship with other ECM components in the perineuronal nets. These authors characterized quadruple brevican/neurocan/tenascin-C/tenascin-R-deficient mice to demonstrate alterations in their excitatory and inhibitory synaptic responses.…”