All-or-none disconnection of pyramidal inputs onto parvalbumin-positive interneurons gates ocular dominance plasticity

Abstract

Disinhibition is an obligatory initial step in the remodeling of cortical circuits by sensory experience. Our investigation on disinhibitory mechanisms in the classical model of ocular dominance plasticity uncovered an unexpected form of experience-dependent circuit plasticity. In the layer 2/3 of mouse visual cortex, monocular deprivation triggers a complete, “all-or-none,” elimination of connections from pyramidal cells onto nearby parvalbumin-positive interneurons (Pyr→PV). This binary form of circuit plasticity is unique, as it is transient, local, and discrete. It lasts only 1 d, and it does not manifest as widespread changes in synaptic strength; rather, only about half of local connections are lost, and the remaining ones are not affected in strength. Mechanistically, the deprivation-induced loss of Pyr→PV is contingent on a reduction of the protein neuropentraxin2. Functionally, the loss of Pyr→PV is absolutely necessary for ocular dominance plasticity, a canonical model of deprivation-induced model of cortical remodeling. We surmise, therefore, that this all-or-none loss of local Pyr→PV circuitry gates experience-dependent cortical plasticity.

A biomarker-authenticated model of schizophrenia implicating NPTX2 loss of function

“…In a complementary study, we examined NPTX2-SEP in mouse visual cortex following monocular deprivation and found a decrease within 24 hours that correlated with “all-or-none” disconnection of ~50% of excitatory synapses from PN to closely proximal PVs in layer 2/3 ( 37 ). In this model, overexpression of NPTX2-SEP blocked disconnection while dominant-negative NPTX2 expressed in adult brain reinstated ocular dominance plasticity and was permissive for PN-PV disconnection.…”

“…Examination of synaptic connectivity in visual cortex of adolescent Nptx2 −/− mice reveals a selective reduction of layer 2/3 PN connectivity with PVs ( 24 ). Moreover, in WT mice, monocular deprivation in adolescent mice results in reduction of connectivity between PN and closely proximal PVs in layer 2/3 with a time course that parallels reduced NPTX2 expression, and NPTX2-SEP overexpression prevents monocular deprivation–induced disconnection of PN-PV ( 37 ). Reciprocally, dominant-negative NPTX2 reinstates ocular dominance plasticity in adult brain, suggesting that dynamic changes of NPTX2 are required to establish new functional excitatory circuits ( 37 ).…”

“…Moreover, in WT mice, monocular deprivation in adolescent mice results in reduction of connectivity between PN and closely proximal PVs in layer 2/3 with a time course that parallels reduced NPTX2 expression, and NPTX2-SEP overexpression prevents monocular deprivation–induced disconnection of PN-PV ( 37 ). Reciprocally, dominant-negative NPTX2 reinstates ocular dominance plasticity in adult brain, suggesting that dynamic changes of NPTX2 are required to establish new functional excitatory circuits ( 37 ). It is compelling to suggest that the diurnal changes of synaptic NPTX2, which are comparable in amplitude to those observed with monocular deprivation, similarly contribute to cortical Hebbian and homeostatic plasticity.…”

Neuronal pentraxin Nptx2 regulates complement activity in the brain

“…While we cannot exclude the possibility that Nptx2 might modulate synapse stability and/or density through binding to AMPA receptors or other (synaptic) interaction partners, the decreased synapse density in Nptx2 KO mice was C1q-dependent. The dynamic redistribution of synaptic Nptx2 in response to behavior, sleep, circadian rhythm, and afferent activity (Severin et al, 2021;Xiao et al, 2021) indicates that Nptx2-C1q might contribute to the precise refinement of circuits that mediate homeostasis of excitability, rhythmicity, and capacity for information processing.…”

“…Nptx2 is expressed as an immediate early gene by excitatory neurons and is particularly important for activity-dependent strengthening of GluA4 AMPA-R containing excitatory synapses on PV-IN (Chang et al, 2010;Sia et al, 2007;Xiao et al, 2017). Ocular dominance plasticity requires NPTX2 (Gu et al, 2013) and monocular deprivation results in rapid shedding of Nptx2 expressed by pyramidal neurons at excitatory synapses on PV-IN in deprived cortex with co-incident disconnection of excitatory synapses coupling pyramidal neurons with PV-IN (Severin et al, 2021). In an AD amyloidosis mouse model, Nptx2 amplifies the effect of amyloid-beta (Aß) to reduce inhibitory circuit function required for gamma rhythmicity (Xiao et al, 2017).…”