Perineuronal nets stabilize the grid cell network

Abstract

Grid cells are part of a widespread network that supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. To reveal the relationship between stable spatial representations and the presence of PNNs we recorded from populations of neurons in adult rats. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells' ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.(9, 11). Once established, the periodic spiking pattern of grid cells is remarkably stable when animals revisit the same environment. Local perturbations of different cell types in MEC cause changes to grid field spike rates or an increased number of out-of-field spikes, but the location of the fields remains unaltered (12)(13)(14). Furthermore, when placed in a different environment, neighboring populations of grid cells show a coherent shift of grid fields (15) that retains their relative spatiotemporal relationships (16). In contrast the hippocampal place cells remap by independently and unpredictably changing their activity. This suggests that the mature grid cell network is more hardwired and less plastic than the hippocampal place cell network.The network that controls grid cell spiking is not yet fully understood, but recurrent inhibition appears to be fundamental to the specific activity of grid cells. Stellate cells, one of the two principal cell types that display grid cell firing (7 ), are connected via parvalbumin expressing (PV + ) inhibitory interneurons (17 , 18). PV + cells account for about 50% of the inhibitory cells in MEC (19), making them the main inhibitory mediator in the local grid cell network. In sensory cortex, PV + cells play a central role in shaping the excitatory activity of principal neurons by regulating the onset of periods of high synaptic plasticity (20). Whether PV + inhibitory neurons in MEC play a similar role for development of the grid cell network remains elusive.A hallmark of maturing PV + cells is that aggregates of specialized extracellular matrix, called perineuronal nets (PNNs), condense on the cell soma and proximal dendrites, leaving openings only for synaptic connections (21). PNNs are believed to help stabilize the activity of PV + cells by supporting synaptic integrity and limiting synaptogenesis, in addition to supporting PV + cell physiology (22). By the time PNNs in sensory cortex are fully mature, plasticity in the local network is strongly reduced. However, juvenile levels of plasticity can be r...

Microglia as hackers of the matrix: sculpting synapses and the extracellular space

“…In line with their role as a synaptic scaffold, PNNs have been proposed as the molecular basis of longterm memory storage [150], and their experimental removal disrupts the consolidation [151,152] and recall [152,153] of various types of remote fear memories. Thus, the heightened plasticity afforded by PNN loss may impair long-term memory fidelity due to interference from new memory traces [92,154,155]. Physiologically, PNNs also protect host cells from neurotoxins such as Aβ 1-42 and oxidative stress [156,157], regulate neuronal excitability [158,159], and augment neuronal firing by reducing membrane capacitance akin to myelin sheaths [160], thereby influencing excitatory-inhibitory balance.…”

Neuron–Oligodendrocyte Communication in Myelination of Cortical GABAergic Cells

“…Critical period plasticity returns when ECM is removed enzymatically by Chondroitinase ABC, suggesting that PNNs act as a brake on experience-dependent plasticity [ 139 , 140 , 141 ]. PNNs may then protect interneurons from sensory over-activation and stabilize cortical networks [ 142 , 143 ], even at the cost of reduced cortical plasticity and deficits in adult skill acquisition [ 142 ].…”

Perineuronal nets affect memory and learning after synapse withdrawal

“…While the hippocampus has been accepted for many years as the central site for place memory, other sites input to the hippocampus and store place information. The entorhinal cortex contains grid cells which connect to hippocampal place neurons, and the cingulate cortex and some subcortical structures are also implicated [50][51][52][53]. It is probable that cortical positional backup memory was responsible for the rapid recovery of memory in the hippocampal focal AcanKO group during the period between HLS and re-exposure to the MWM.…”

“…In both these groups PNNs were completely or partially disrupted in the cortical regions lateral to the hippocampus, which is where cortical place memory is found. It is probable that the backup memory store outside the hippocampus does not function efficiently in the absence of PNNS, probably due to the instability in cortical positional networks seen after PNN removal [53].…”