Disruption of perineuronal nets increases the frequency of sharp wave ripple events

Abstract

Hippocampal sharp wave ripples (SWRs) represent irregularly occurring synchronous neuronal population events that are observed during phases of rest and slow wave sleep. SWR activity that follows learning involves sequential replay of training-associated neuronal assemblies and is critical for systems level memory consolidation. SWRs are initiated by CA2 or CA3 pyramidal cells (PCs) and require initial excitation of CA1 PCs as well as participation of parvalbumin (PV) expressing fast spiking (FS) inhibitory interneurons. These interneurons are relatively unique in that they represent the major neuronal cell type known to be surrounded by perineuronal nets (PNNs), lattice like structures composed of a hyaluronin backbone that surround the cell soma and proximal dendrites. Though the function of the PNN is not completely understood, previous studies suggest it may serve to localize glutamatergic input to synaptic contacts and thus influence the activity of ensheathed cells. Noting that FS PV interneurons impact the activity of PCs thought to initiate SWRs, and that their activity is critical to ripple expression, we examine the effects of PNN integrity on SWR activity in the hippocampus. Extracellular recordings from the stratum radiatum of horizontal murine hippocampal hemisections demonstrate SWRs that occur spontaneously in CA1.As compared with vehicle, pre-treatment (120 min) of paired hemislices with hyaluronidase, which cleaves the hyaluronin backbone of the PNN, decreases PNN integrity and increases SWR frequency. Pre-treatment with chondroitinase, which cleaves PNN side chains, also increases SWR frequency. Together, these data contribute to an emerging appreciation of extracellular matrix as a regulator of neuronal plasticity and suggest that one function of mature perineuronal nets could be to modulate the frequency of SWR events. K E Y W O R D Schondrotinase, hippocampus, hyaluronidase, protease, PV interneuron

A Role for Matrix Metalloproteases in Antidepressant Efficacy

“…Since each PV interneuron can contact hundreds of pyramidal cells (Andersen et al, 2006), PNN disruption may influence pyramidal cell activity at the population level. Consistent with this, recent findings in rodents show that PNN diminution has the potential to enhance both the power of gamma oscillations and the frequency of sharp wave ripple events (Lensjo et al, 2017b; Sun et al, 2018). Similarly, chronic venlafaxine treatment stimulates PNN diminution and an MMP-9-dependent increase in carbachol-induced gamma oscillatory power in ex vivo hippocampal slices (Alaiyed et al, 2019).…”

Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population Dynamics

“…In terms of flexibility, PNN abundance is modulated by proteolytic processing. While experimental studies often utilize hyaluronidase or chondroitinase to affect PNN degradation [ 24 , 47 , 48 ], MMPs and ADAMTS proteins likely represent important physiological modulators of the PNN [ 1 ]. This is supported by recent work showing that PNN is more abundantly expressed in juvenile MMP-9-null mice [ 49 ].…”

“…Though PNN staining in the hippocampus is less robust than that in the visual cortex [ 17 ], reduced PV activity could nonetheless influence population activity in this brain region as well. In recent work, we have observed that ex vivo treatment of hippocampal slices with hyaluronidase or chondroitinase can increase the frequency of sharp-wave ripple (SWR) events [ 48 ]. The sharp wave reflects depolarization of CA1 pyramidal cells by synchronous discharge of CA3 axonal inputs [ 148 ].…”

Structural Changes Observed in the Piriform Cortex in a Rat Model of Pre-motor Parkinson’s Disease

“…Although the role of PNNs surrounding PC pyramidal cells is undetermined, PNNs have been shown to restrict synaptic plasticity in the hippocampal CA2 pyramidal cells (Carstens et al, 2016). Loss of PNNs may also render interneurons more susceptible to oxidative stress due to astrocytic activation as early as 8 days after surgery, potentially leading to a reduction of PV mRNA expression and a potential disruption of oscillatory activity as previously shown in the hippocampus (Yamada et al, 2015; Sun et al, 2018). The number of GAD-immunopositive neurones in the PC of the pre-motor model was similar to that in the sham animals, suggesting a downregulation of CBPs rather than neuronal death.…”