Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c

Rajkovich, Kacey; Loerwald, Kristofer W.; Hale, Carly F.; Hess, Carolyn T.; Gibson, Jay R.; Huber, Kimberly M.

doi:10.1016/j.neuron.2016.11.022

Cited by 46 publications

(58 citation statements)

References 34 publications

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“…Since many of the MEF2C-regulated genes expressed in CNS neurons respond to neuronal activation with downregulation of excitatory synaptic strength (Flavell et al, 2006;Rajkovich et al, 2017), we also examined MEF2C target gene expression in response to SD or RS. We found that the downregulated DEGs shared by SD and RS were enriched for neuronal genes downregulated by Mef2c loss of function as previously 15 observed in a conditional knockout of neuronal Mef2c, Mef2c (Harrington et al, 2016).…”

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confidence: 99%

An essential role for MEF2C in the cortical response to loss of sleep

Bjorness

Kulkarni

Rybalchenko

et al. 2020

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Neuronal activity and gene expression in response to the loss of sleep can provide a window into the enigma of sleep function. Sleep loss is associated with brain 25 differential gene expression, an increase in pyramidal cell mEPSC frequency and amplitude, and a characteristic rebound and resolution of slow wave sleep-slow wave activity (SWS-SWA). However, the molecular mechanism(s) mediating the sleep loss response are not well understood. We show that sleep-loss regulates MEF2C phosphorylation, a key mechanism regulating MEF2C transcriptional 30 activity, and that MEF2C function in postnatal excitatory forebrain neurons is required for the biological events in response to sleep loss. These include altered gene expression, the increase and recovery of synaptic strength, and the rebound and resolution of SWS-SWA, which implicate MEF2C as an essential regulator of sleep function. 35 One Sentence Summary: MEF2C is critical to the response to sleep loss. Main Text:Sleep abnormalities are commonly observed in numerous neurological disorders, 40 including autism spectrum disorder, major depressive disorder, bipolar disorder, posttraumatic stress disorder, neurodegenerative disorders and many others, but our understanding of sleep need and its regulation and resolution is poorly understood. Following an extended period of waking, or sleep deprivation (SD), the mammalian cortex shows an altered pattern of EEG activity characterized by rebound slow wave power 45 (delta power in the frequency range of 0.5-4.5Hz) during the ensuing slow wave sleep 2

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confidence: 99%

An essential role for MEF2C in the cortical response to loss of sleep

Bjorness

Kulkarni

Rybalchenko

et al. 2020

Preprint

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“…Changes in excitatory (E) and/or inhibitory (I) synaptic transmission are associated with numerous neuropsychiatric disorders, including ASD (Antoine et al, 2019; Garber, 2007; Zoghbi and Bear, 2012). Conditional knockout of Mef2c alters somatosensory cortex (SSCtx) pyramidal neuron E/I synaptic transmission (Harrington et al, 2016; Rajkovich et al, 2017). In the global Mef2c -Hets (p35-p40), gross structural organization of barrel fields within cortical layer 4 of the SSCtx appeared normal (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…S3B) or effects on presynaptic functions of local inputs (Fig. 3C,D), and might represent a compensatory effect of long-range connections (Rajkovich et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…Constitutively-active MEF2C can promote glutamatergic synapse elimination, a process requiring the RNA-binding function of the Fragile X Mental Retardation protein (FMRP) and several other factors (Flavell et al, 2006; Pfeiffer et al, 2010; Tsai et al, 2012; Zang et al, 2013). Conditional knockout of Mef2c in neuronal populations within the mouse brain produces a myriad of severe behavioral and synaptic phenotypes, which emphasizes the importance of this gene in healthy brain development (Adachi et al, 2015; Barbosa et al, 2008; Harrington et al, 2016; Li et al, 2008; Rajkovich et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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MEF2C hypofunction in neuronal and neuroimmune populations cooperate to produce MEF2C haploinsufficiency syndrome-like behaviors in mice

Harrington

Bridges

Blankenship

et al. 2019

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Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C 2 haploinsufficiency syndrome (MCHS). Here, we show that MCHS-associated missense mutations cluster 3 in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global 4 Mef2c heterozygous mice (Mef2c-Het) display numerous MCHS-like behaviors, including autism-related 5 behaviors, as well as deficits in cortical excitatory synaptic transmission. We find that hundreds of genes 6 are dysregulated in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory 7 neuron genes. In addition, we observe an enrichment of upregulated microglial genes, but not due to 8 neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain 9 excitatory neurons reproduces a subset of the Mef2c-Het phenotypes, while conditional Mef2c 10 heterozygosity in microglia reproduces social deficits and repetitive behavior. Together our findings 11 suggest that MEF2C regulates typical brain development and function through multiple cell types, 12 including excitatory neuronal and neuroimmune populations.13 14

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“…Within prenatal development MEF2C has the potential to be a transcriptional regulator of a number of autism-associated genes -MEF2C binding motifs are enriched in upstream regions of genes within prenatal gene co-expression modules that harbor a number of autism-associated genes 4 . Congruent with the idea that MEF2C is important for many prenatal neurodevelopmental processes, other work has shown it is involved in neurogenesis, cell differentiation, maturation, and migration [61][62][63] as well as having later roles to play in experiencedependent synaptic development and cell death 52,53,64,65 . MEF2C is also a known downstream target of the androgen receptor (AR), thus making it highly susceptible to androgen-dependent transcriptional influence 43 .…”

Section: Discussionmentioning

confidence: 99%

Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

Lombardo

Auyeung

Pramparo

et al. 2018

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Many early-onset neurodevelopmental conditions such as autism affect males more frequently than females and affect corresponding domains such as social cognition, social-communication, language, emotion, and reward. Testosterone is well-known for its role as a sex-related biological mechanism and affects these conditions and domains of functioning. Developmentally, testosterone may sex-differentially impact early fetal brain development by influencing early neuronal development and synaptic mechanisms behind cortical circuit formation, particularly for circuits that later develop specialized roles in such cognitive domains. Here we find that variation in fetal testosterone (FT) exerts sex-specific effects on later adolescent functional connectivity between social brain default mode network (DMN) subsystems. Increased FT is associated with dampening of functional connectivity between DMN subsystems in adolescent males, but has no effect in females. To isolate specific prenatal neurobiological mechanisms behind this effect, we examined changes in gene expression identified following a treatment with a potent androgen, dihydrotestosterone (DHT) in an in-vitro model of human neural stem cell (hNSC). We previously showed that DHT-dysregulates genes enriched with known syndromic causes for autism and intellectual disability. DHT dysregulates genes in hNSCs involved in early neurodevelopmental processes such as neurogenesis, cell differentiation, regionalization, and pattern specification. A significant number of these DHT-dysregulated genes shows spatial expression patterns in the adult brain that highly correspond to the spatial layout of the cortical midline DMN subsystem. These DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation/inhibition imbalance. Focusing on MEF2C, we find replicable upregulation of expression after DHT treatment as well as dysregulated expression in induced pluripotent stem cells and neurons of individuals with autism. This work highlights sexspecific prenatal androgen influence on social brain DMN circuitry and autism-related mechanisms and suggests that such influence may impact early neurodevelopmental processes (e.g., neurogenesis, cell differentiation) and later developing synaptic processes.

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Experience-Dependent and Differential Regulation of Local and Long-Range Excitatory Neocortical Circuits by Postsynaptic Mef2c

Cited by 46 publications

References 34 publications

An essential role for MEF2C in the cortical response to loss of sleep

An essential role for MEF2C in the cortical response to loss of sleep

MEF2C hypofunction in neuronal and neuroimmune populations cooperate to produce MEF2C haploinsufficiency syndrome-like behaviors in mice

Sex-specific impact of prenatal androgens on intrinsic functional connectivity between social brain default mode subsystems

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