Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice

Ma, Xiaokuang; Wei, Jing; Cui, Yuehua; Xia, Baomei; Zhang, Le; Nehme, Antoine; Zuo, Yi; Ferguson, Deveroux; Levitt, Pat; Qiu, Shenfeng

doi:10.1093/cercor/bhab323

Cited by 7 publications

(16 citation statements)

References 112 publications

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“…Alteration within the MET receptor tyrosine kinase may be a critical contributing genetic factor in autism, with variable disruption of post-natal neurological plasticity, depending on cell context ( Eagleson et al, 2017 ). Curiously, prolonging MET signalling for 2 weeks in developing mice results in repetitive actions and social impairment ( Ma et al, 2021 ).…”

Section: Update - Abnormal Dorsal Stream Development and Connectivity In Autismmentioning

confidence: 99%

Neural Mechanisms of Visual Motion Anomalies in Autism: A Two-Decade Update and Novel Aetiology

Spiteri

Crewther

2021

Front. Neurosci.

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The 21st century has seen dramatic changes in our understanding of the visual physio-perceptual anomalies of autism and also in the structure and development of the primate visual system. This review covers the past 20 years of research into motion perceptual/dorsal stream anomalies in autism, as well as new understanding of the development of primate vision. The convergence of this literature allows a novel developmental hypothesis to explain the physiological and perceptual differences of the broad autistic spectrum. Central to these observations is the development of motion areas MT+, the seat of the dorsal cortical stream, central area of pre-attentional processing as well as being an anchor of binocular vision for 3D action. Such development normally occurs via a transfer of thalamic drive from the inferior pulvinar → MT to the anatomically stronger but later-developing LGN → V1 → MT connection. We propose that autistic variation arises from a slowing in the normal developmental attenuation of the pulvinar → MT pathway. We suggest that this is caused by a hyperactive amygdala → thalamic reticular nucleus circuit increasing activity in the PIm → MT via response gain modulation of the pulvinar and hence altering synaptic competition in area MT. We explore the probable timing of transfer in dominance of human MT from pulvinar to LGN/V1 driving circuitry and discuss the implications of the main hypothesis.

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Section: Update - Abnormal Dorsal Stream Development and Connectivity In Autismmentioning

confidence: 99%

Neural Mechanisms of Visual Motion Anomalies in Autism: A Two-Decade Update and Novel Aetiology

Spiteri

Crewther

2021

Front. Neurosci.

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“…Accumulating evidence underscores a key role for the MET receptor tyrosine kinase (MET) in the development of discrete circuits within the forebrain. In cortex, abundant MET expression coincides with the period of peak synaptogenesis, and MET signaling modulates dendritic and synapse development and maturation [21][22][23][24][25][26]. Prolonging or eliminating MET expression alters the timing of critical period plasticity for ocular dominance, shifting the critical period later or earlier, respectively [24].…”

Section: Introductionmentioning

confidence: 99%

“…Prolonging or eliminating MET expression alters the timing of critical period plasticity for ocular dominance, shifting the critical period later or earlier, respectively [24]. Additionally, prolonging MET expression during a critical period for social cognition alters social behavior in adult mice [25]. Finally, adult mice in which Met had been conditionally deleted embryonically in all neural cells or in cells arising from the dorsal pallium only exhibit contextual fear learning deficits [27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Developmental and molecular contributions to contextual fear memory emergence in mice

Lanjewar

Levitt

Eagleson

2023

Preprint

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Cognitive impairment is a common phenotype of neurodevelopmental disorders, but how these deficits arise remains elusive. Determining the onset of discrete cognitive capabilities facilitates studies in probing mechanisms underlying their emergence. The present study analyzed the emergence of contextual fear memory persistence (7-day memory retention) and remote memory (30-day memory retention). There was a rapid transition from postnatal day (P) 20 to P21, in which memory persistence emerged in C57Bl/6J male and female mice. Remote memory was present at P23, but expression was not robust compared to pubertal and adult mice. To address a potential molecular mechanism, the present study examined the MET receptor tyrosine kinase (MET), which when deleted results in fear memory deficits in adult mice and regulates timing of critical period in the visual cortex, positioning it as a regulator for onset of contextual fear memory. Sustaining Met past the normal window of peak cortical expression or deleting Met did not alter the timing of emergence of persistence or remote memory capabilities. However, failure to exhibit fear memory occurred by P90 in mice with reduction or deletion of Met. Remarkably, the number of FOS-expressing infragranular neurons in medial prefrontal cortex (mPFC) did not increase with contextual conditioning at P35 but exhibited enhanced activation at P90. Additionally, MET-expressing neurons were preferentially recruited at P90 compared to P35 during fear memory expression. The studies demonstrate a developmental profile of contextual fear memory capabilities. Further, developmental disruption of Met leads to a delayed functional deficit that arises in adulthood.

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“…Selective deletion of Met in cells that arise from the dorsal pallium results in precocious electrophysiological and molecular maturation of excitatory synapses. In contrast, extending cortical Met expression past its normal temporal decline results in synapses remaining in a more immature state (K. Chen et al., 2021 ; Ma et al., 2022 ). Thus, the timing of the downregulation of MET expression modulates the timing of synapse maturation and stabilization, with functional consequences at the circuit and behavioral level.…”

Section: Introductionmentioning

confidence: 99%

“…For example, the critical period for ocular dominance in the primary visual cortex (V1) is closed prematurely or opened later by deleting or extending Met expression, respectively (K. Chen et al., 2021 ). Disruption of the temporal regulation of MET also impacts medial prefrontal cortex (mPFC)‐mediated functions, including social cognition (Ma et al., 2022 ) and contextual fear memory (Heun‐Johnson & Levitt, 2017 ; Thompson & Levitt, 2015 ; Xia et al., 2021 ). Notably, while deficits in contextual fear memory are apparent in adults when Met expression is reduced or eliminated developmentally from all neural cells (Heun‐Johnson & Levitt, 2017 ; Thompson & Levitt, 2015 ) or from cells arising from the dorsal pallium (Xia et al., 2021 ), there is no effect on the onset of expression of contextual fear memory in weanling mice (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Subclass‐specific expression patterns of MET receptor tyrosine kinase during development in medial prefrontal and visual cortices

Lanjewar

Jagetia

Khan

et al. 2022

J of Comparative Neurology

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Met encodes a receptor tyrosine kinase (MET) that is expressed during development and regulates cortical synapse maturation. Conditional deletion of Met in the nervous system during embryonic development leads to deficits in adult contextual fear learning, a medial prefrontal cortex (mPFC)‐dependent cognitive task. MET also regulates the timing of critical period plasticity for ocular dominance in primary visual cortex (V1). However, the underlying circuitry responsible remains unknown. Therefore, this study determines the broad expression patterns of MET throughout postnatal development in mPFC and V1 projection neurons (PNs), providing insight into similarities and differences in the neuronal subtypes and temporal patterns of MET expression between cortical areas. Using a transgenic mouse line that expresses green fluorescent protein (GFP) in Met+ neurons, immunofluorescence and confocal microscopy were performed to visualize MET‐GFP+ cell bodies and PN subclass‐specific protein markers. Analyses reveal that the MET expression is highly enriched in infragranular layers of mPFC, but in supragranular layers of V1. Interestingly, temporal regulation of the percentage of MET+ neurons across development not only differs between cortical regions but also is distinct between lamina within a cortical region. Further, MET is expressed predominantly in the subcerebral PN subclass in mPFC, but the intratelencephalic PN subclass in V1. The data suggest that MET signaling influences the development of distinct circuits in mPFC and V1 that underlie subcerebral and intracortical functional deficits following Met deletion, respectively.

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Disrupted Timing of MET Signaling Derails the Developmental Maturation of Cortical Circuits and Leads to Altered Behavior in Mice

Cited by 7 publications

References 112 publications

Neural Mechanisms of Visual Motion Anomalies in Autism: A Two-Decade Update and Novel Aetiology

Neural Mechanisms of Visual Motion Anomalies in Autism: A Two-Decade Update and Novel Aetiology

Developmental and molecular contributions to contextual fear memory emergence in mice

Subclass‐specific expression patterns of MET receptor tyrosine kinase during development in medial prefrontal and visual cortices

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