Author Correction: Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible

Goel, Anubhuti; Cantu, Daniel A.; Guilfoyle, Janna; Chaudhari, Gunvant; Newadkar, Aditi; Todisco, Barbara; Alba, Diego de; Kourdougli, Nazim; Schmitt, Lauren; Pedapati, Ernest V.; Erickson, Craig A.; Portera‐Cailliau, Carlos

doi:10.1038/s41593-018-0273-3

Cited by 5 publications

(4 citation statements)

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“…(vi) Finally, various phenotypic characteristics of Bdnf Pax2 KO mice are reminiscent of mouse models relevant to neurodevelopmental disorders, such as ASD. These include reduced PV-IN labeling (Takano, 2015;Pirone et al, 2018;Goel et al, 2019), elevation of Arc levels (Korb and Finkbeiner, 2011;Goel et al, 2019), increased fEPSPs (Mohn et al, 2014), as well as elevated corticosterone levels (Das et al, 2019). Also, a mouse line deficient in adenomatous polyposis coli protein, a key regulator of synapse maturation (Hickman et al, 2015), also developed an autistic phenotype (Mohn et al, 2014;Alexander et al, 2020).…”

Section: Bdnf Pax2 Kos Exhibit Diminished Pv-in Dendritic Outgrowth Lmentioning

confidence: 99%

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Eckert

Marchetta

Manthey

et al. 2021

Front. Mol. Neurosci.

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Numerous studies indicate that deficits in the proper integration or migration of specific GABAergic precursor cells from the subpallium to the cortex can lead to severe cognitive dysfunctions and neurodevelopmental pathogenesis linked to intellectual disabilities. A different set of GABAergic precursors cells that express Pax2 migrate to hindbrain regions, targeting, for example auditory or somatosensory brainstem regions. We demonstrate that the absence of BDNF in Pax2-lineage descendants of BdnfPax2KOs causes severe cognitive disabilities. In BdnfPax2KOs, a normal number of parvalbumin-positive interneurons (PV-INs) was found in the auditory cortex (AC) and hippocampal regions, which went hand in hand with reduced PV-labeling in neuropil domains and elevated activity-regulated cytoskeleton-associated protein (Arc/Arg3.1; here: Arc) levels in pyramidal neurons in these same regions. This immaturity in the inhibitory/excitatory balance of the AC and hippocampus was accompanied by elevated LTP, reduced (sound-induced) LTP/LTD adjustment, impaired learning, elevated anxiety, and deficits in social behavior, overall representing an autistic-like phenotype. Reduced tonic inhibitory strength and elevated spontaneous firing rates in dorsal cochlear nucleus (DCN) brainstem neurons in otherwise nearly normal hearing BdnfPax2KOs suggests that diminished fine-grained auditory-specific brainstem activity has hampered activity-driven integration of inhibitory networks of the AC in functional (hippocampal) circuits. This leads to an inability to scale hippocampal post-synapses during LTP/LTD plasticity. BDNF in Pax2-lineage descendants in lower brain regions should thus be considered as a novel candidate for contributing to the development of brain disorders, including autism.

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Section: Bdnf Pax2 Kos Exhibit Diminished Pv-in Dendritic Outgrowth Lmentioning

confidence: 99%

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Eckert

Marchetta

Manthey

et al. 2021

Front. Mol. Neurosci.

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“…Therefore, targeted NO-GC β1 mRNA for analysis of expression profiles. The recently observed potentiating influence of altered cGMP generator activity on LTP and synaptic AMPA receptor transport activity (Nelissen et al, 2021(Nelissen et al, , 2022) moreover motivated us to correlate levels of cGMP generators with changes of cytoplasmic Arc/ Arg3.1, the mRNA of which is targeted to dendrites during LTP/LTD changes in response to neuronal activity (Korb and Finkbeiner, 2011;Goel et al, 2019). In situ hybridizations of NO-GC β1, GC-A, and Arc/ Arg3.1 mRNA were analyzed in brain sections and quantified in the CA1 region of the hippocampus according to previously established protocols (Matt et al, 2018;Eckert et al, 2021; Figure 4).…”

Section: Deletion Of Mr And/or Gr In the Hippocampus Differentially A...mentioning

confidence: 99%

Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling

Calis

Hess²,

Marchetta³

et al. 2023

Front. Mol. Neurosci.

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The complex mechanism by which stress can affect sensory processes such as hearing is still poorly understood. In a previous study, the mineralocorticoid (MR) and/or glucocorticoid receptor (GR) were deleted in frontal brain regions but not cochlear regions using a CaMKIIα-based tamoxifen-inducible CreERT2/loxP approach. These mice exhibit either a diminished (MRTMXcKO) or disinhibited (GRTMXcKO) auditory nerve activity. In the present study, we observed that mice differentially were (MRTMXcKO) or were not (GRTMXcKO) able to compensate for altered auditory nerve activity in the central auditory pathway. As previous findings demonstrated a link between central auditory compensation and memory-dependent adaptation processes, we analyzed hippocampal paired-pulse facilitation (PPF) and long-term potentiation (LTP). To determine which molecular mechanisms may impact differences in synaptic plasticity, we analyzed Arc/Arg3.1, known to control AMPA receptor trafficking, as well as regulators of tissue perfusion and energy consumption (NO-GC and GC-A). We observed that the changes in PPF of MRTMXcKOs mirrored the changes in their auditory nerve activity, whereas changes in the LTP of MRTMXcKOs and GRTMXcKOs mirrored instead the changes in their central compensation capacity. Enhanced GR expression levels in MRTMXcKOs suggest that MRs typically suppress GR expression. We observed that hippocampal LTP, GC-A mRNA expression levels, and ABR wave IV/I ratio were all enhanced in animals with elevated GR (MRTMXcKOs) but were all lower or not mobilized in animals with impaired GR expression levels (GRTMXcKOs and MRGRTMXcKOs). This suggests that GC-A may link LTP and auditory neural gain through GR-dependent processes. In addition, enhanced NO-GC expression levels in MR, GR, and MRGRTMXcKOs suggest that both receptors suppress NO-GC; on the other hand, elevated Arc/Arg3.1 levels in MRTMXcKOs and MRGRTMXcKOs but not GRTMXcKOs suggest that MR suppresses Arc/Arg3.1 expression levels. Conclusively, MR through GR inhibition may define the threshold for hemodynamic responses for LTP and auditory neural gain associated with GC-A.

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“…An excitation/inhibition imbalance is also considered to be a characteristic feature of ASD, which is accompanied by reduced PV-IN labeling ( Takano and Matsui, 2015 ; Pirone et al, 2018 ; Goel et al, 2019 ), elevated levels of the activity-related gene Arg3.1/Arc ( Korb and Finkbeiner, 2011 ; Goel et al, 2019 ; Eckert et al, 2021 ), or by increased fEPSPs ( Mohn et al, 2014 ). A reduced inhibition linked with reduced levels of GABA-synthetisising enzymes and GABA receptors was observed in the brain of patients with ASD ( Fatemi et al, 2002 , 2009 , 2010 ; Reynell and Harris, 2013 ; Schur et al, 2016 ; Cukier et al, 2020 ).…”

Section: Altered Excitation and Inhibition Following Diminished Fast Auditory Processing Linked To ‘Central’ Hearing Lossmentioning

confidence: 99%

Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition

Knipper

Singer

Schwabe

et al. 2022

Front. Neural Circuits

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Neuronal hyperexcitability in the central auditory pathway linked to reduced inhibitory activity is associated with numerous forms of hearing loss, including noise damage, age-dependent hearing loss, and deafness, as well as tinnitus or auditory processing deficits in autism spectrum disorder (ASD). In most cases, the reduced central inhibitory activity and the accompanying hyperexcitability are interpreted as an active compensatory response to the absence of synaptic activity, linked to increased central neural gain control (increased output activity relative to reduced input). We here suggest that hyperexcitability also could be related to an immaturity or impairment of tonic inhibitory strength that typically develops in an activity-dependent process in the ascending auditory pathway with auditory experience. In these cases, high-SR auditory nerve fibers, which are critical for the shortest latencies and lowest sound thresholds, may have either not matured (possibly in congenital deafness or autism) or are dysfunctional (possibly after sudden, stressful auditory trauma or age-dependent hearing loss linked with cognitive decline). Fast auditory processing deficits can occur despite maintained basal hearing. In that case, tonic inhibitory strength is reduced in ascending auditory nuclei, and fast inhibitory parvalbumin positive interneuron (PV-IN) dendrites are diminished in auditory and frontal brain regions. This leads to deficits in central neural gain control linked to hippocampal LTP/LTD deficiencies, cognitive deficits, and unbalanced extra-hypothalamic stress control. Under these conditions, a diminished inhibitory strength may weaken local neuronal coupling to homeostatic vascular responses required for the metabolic support of auditory adjustment processes. We emphasize the need to distinguish these two states of excitatory/inhibitory imbalance in hearing disorders: (i) Under conditions of preserved fast auditory processing and sustained tonic inhibitory strength, an excitatory/inhibitory imbalance following auditory deprivation can maintain precise hearing through a memory linked, transient disinhibition that leads to enhanced spiking fidelity (central neural gain⇑) (ii) Under conditions of critically diminished fast auditory processing and reduced tonic inhibitory strength, hyperexcitability can be part of an increased synchronization over a broader frequency range, linked to reduced spiking reliability (central neural gain⇓). This latter stage mutually reinforces diminished metabolic support for auditory adjustment processes, increasing the risks for canonical dementia syndromes.

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Author Correction: Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible

Cited by 5 publications

References 0 publications

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Deletion of BDNF in Pax2 Lineage-Derived Interneuron Precursors in the Hindbrain Hampers the Proportion of Excitation/Inhibition, Learning, and Behavior

Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling

Disturbed Balance of Inhibitory Signaling Links Hearing Loss and Cognition

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