A comprehensive atlas of perineuronal net distribution and colocalization with parvalbumin in the adult mouse brain

Lupori, Leonardo; Totaro, Valentino; Cornuti, Sara; Ciampi, Luca; Carrara, Fabio; Grilli, Edda; Viglione, Aurelia; Tozzi, Francesca; Putignano, Elena; Mazziotti, Raffaele; Amato, Giuseppe; Gennaro, Claudio; Tognini, Paola; Pizzorusso, Tommaso

doi:10.1016/j.celrep.2023.112788

Cited by 21 publications

(21 citation statements)

References 86 publications

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“…Mann-Whitney test). The PV/WFA overlap in PVcre control animals (63.64% ± 9.41%) is in agreement with a recent, extensive study on the distribution of PNNs in the mouse brain (Lupori et al, 2023).…”

Section: Resultssupporting

confidence: 92%

Deciphering the Role of Aggrecan in Parvalbumin Interneurons: Unexpected Outcomes from a Conditional ACAN Knockout That Eliminates WFA+ Perineuronal Nets

Grødem,

Thompson,

Røe

et al. 2024

Preprint

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The transition from juvenile to adult is accompanied by the maturation of inhibitory parvalbumin-positive (PV+) neurons and reduced plasticity. This transition involves the formation of perineuronal nets (PNNs), a dense configuration of the extracellular matrix that predominantly envelops parvalbumin-positive (PV+) neurons. Aggrecan, a proteoglycan encoded by the ACAN gene, has been shown to have a key role in the PNNs as knock-out of ACAN in the adult brain reactivates juvenile plasticity, but the contribution of different cell populations is unknown. Here, we establish and characterize a mouse model in which ACAN is selectively knocked out (KO) in PV+ neurons (ACANflx/PVcre). Moreover, we develop a viral tool to perform similar cell-type directed KO in adult mice. Both models are compared with the traditional method of PNN removal, namely enzymatic degradation of PNNs with Chondroitinase ABC (chABC). We show that PV+ neurons in adult ACANflx/PVcre mice do not produce PNNs that are labeled by Wisteria floribunda agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons in the visual cortex (V1) and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo chABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. This suggests compensatory mechanisms in the germline KO. Indeed, qPCR of bulk tissue indicates that other PNN components are expressed at higher levels in the KO animals. Finally, we perform memory- and behavioral testing to see if the lack of ACAN from PV+ neurons throughout development affected stereotypic behaviors and memory processing. ACANflx/PVcre mice have learning and memory abilities similar to controls, but use bold search strategies during navigation in the Morris water maze. The low level of anxiety-related behavior is confirmed in an open field and zero maze, where they spent nearly twice the time in open areas.

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Section: Resultssupporting

confidence: 92%

Deciphering the Role of Aggrecan in Parvalbumin Interneurons: Unexpected Outcomes from a Conditional ACAN Knockout That Eliminates WFA+ Perineuronal Nets

Grødem,

Thompson,

Røe

et al. 2024

Preprint

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“…One of underlying mechanisms seems to be mediated by the reduction in expression of PV and Kcnc1/K v 3, the potassium channels important for fast-spiking of PV neurons. Previous studies have reported similar changes after PNN degradation by chondroitinase ABC (Willis et al, 2022; Lupori et al, 2023). The amount of parvalbumin in PV interneurons increases with their maturation (Bitzenhofer et al, 2020; Lupori et al, 2023) and has been shown to affect the acquisition of their mature phenotypes (Yang et al, 2014).…”

Section: Discussionsupporting

confidence: 66%

Section: Ncan Depletion Increases Neuronal Activitysupporting

confidence: 68%

“…The amount of parvalbumin in PV interneurons increases with their maturation (Bitzenhofer et al, 2020;Lupori et al, 2023) and has been shown to affect the acquisition of their mature phenotypes (Yang et al, 2014). Thus, it is plausible that Ncan knockdown shifts the excitation-inhibition ratio towards excitation, modulating activity of PV cells.…”

Section: Ncan Depletion Increases Neuronal Activitymentioning

confidence: 99%

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Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons

Baidoe-Ansah,

Mirzapourdelavar,

Aleshin

et al. 2024

Preprint

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The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, nodes of Ranvier and the AIS, highlighting its potential role in regulation of axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AIS and in the regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulated Aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of Ankyrin-G in the AIS particularly in excitatory neurons, and with the elevated expression of Nav1.6 channels. Our results suggest that Ncan regulate expression of key proteins in PNNs and AISs and provide new insights into its role in the fine-tuning of neuronal functions.

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“…Supporting this, PNN energy across brain regions is anti-correlated with the expression of genes related to processes involved in synaptic plasticity, including postsynaptic density organization, regulation of synapse structure, and learning and memory. 126 Ultimately, by identifying coordinated transcriptomic and spatial coding changes in aged MEC, this work motivates elucidating the role of Hapln4 and other age-modulated, stability-correlated genes in MEC IN synaptic plasticity, which may be a critical determinant of MEC-HPC spatial coding and spatial memory decline in aging.…”

Section: Discussionmentioning

confidence: 99%

Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex

Herber,

Pratt,

Shea

et al. 2024

Preprint

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SummaryAcross species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveragedin vivoelectrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 458 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial firing stability. These genes were enriched among interneurons and related to synaptic transmission. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging.

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A comprehensive atlas of perineuronal net distribution and colocalization with parvalbumin in the adult mouse brain

Cited by 21 publications

References 86 publications

Deciphering the Role of Aggrecan in Parvalbumin Interneurons: Unexpected Outcomes from a Conditional ACAN Knockout That Eliminates WFA+ Perineuronal Nets

Deciphering the Role of Aggrecan in Parvalbumin Interneurons: Unexpected Outcomes from a Conditional ACAN Knockout That Eliminates WFA+ Perineuronal Nets

Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons

Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex

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