CA1 Neurons Acquire Rett Syndrome Phenotype After Brief Activation of Glutamatergic Receptors: Specific Role of mGluR1/5

Balakrishnan, Saju; Mironov, S. L.

doi:10.3389/fncel.2018.00363

Cited by 8 publications

(21 citation statements)

References 40 publications

(80 reference statements)

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“…Notably, we have proposed mGlu7 as a novel target for Rett syndrome due to decreased mGlu7 expression in RTT autopsy tissue and mGlu7's role in promoting synaptic plasticity (27). Activation of mGlu7 can regulate release of glutamate and GABA, both of which have been shown to contribute to RTT-related phenotypes (28)(29)(30). Taken together with the fact that Grm7 knockout mice recapitulate phenotypes often observed in neurodevelopmental disorders (12), it was likely that GRM7 clinical variants would lead to loss-of-function of the mGlu7 receptor.…”

Section: Discussionmentioning

confidence: 99%

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

Fisher¹,

Alhashim²,

Buch³

et al. 2021

JCI Insight

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The metabotropic glutamate receptor 7 (mGlu 7 ) is a G protein–coupled receptor that has been recently linked to neurodevelopmental disorders. This association is supported by the identification of GRM7 variants in patients with autism spectrum disorder, attention deficit hyperactivity disorder, and severe developmental delay. One GRM7 mutation previously reported in 2 patients results in a single amino acid change, I154T, within the mGlu 7 ligand-binding domain. Here, we report 2 new patients with this mutation who present with severe developmental delay and epilepsy. Functional studies of the mGlu 7 -I154T mutant reveal that this substitution resulted in significant loss of mGlu 7 protein expression in HEK293A cells and in mice. We show that this occurred posttranscriptionally at the level of protein expression and trafficking. Similar to mGlu 7 –global KO mice, mGlu 7 -I154T animals exhibited reduced motor coordination, deficits in contextual fear learning, and seizures. This provides functional evidence that a disease-associated mutation affecting the mGlu 7 receptor was sufficient to cause neurological dysfunction in mice and further validates GRM7 as a disease-causing gene in the human population.

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Section: Discussionmentioning

confidence: 99%

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

Fisher¹,

Alhashim²,

Buch³

et al. 2021

JCI Insight

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show abstract

“…Transduction was done two days after plating slices and the experiments were performed from P7 on, after expression of the sensor reached the steady state. The probes targeted to the glia and neurons reported similar changes in all experimental protocols used, see also ( Balakrishnan & Mironov, 2018a ; Balakrishnan & Mironov, 2018b ; Balakrishnan & Mironov, 2018 ). Because the sensors are expressed in the plasma membranes of neurons or astrocytes and exposed to the thin extracellular space (<100 nm wide), they should sense the same ambient glutamate.…”

Section: Methodsmentioning

confidence: 78%

“…All experimental procedures used are essentially the same as employed in previous studies ( Balakrishnan & Mironov, 2018a ; Balakrishnan & Mironov, 2018b ; Balakrishnan & Mironov, 2018 ) and only briefly recapitulated below.…”

Section: Methodsmentioning

confidence: 99%

“…We indeed measured elevated ambient glutamate levels in RTT ( Balakrishnan & Mironov, 2018a ). This apparently set conditions to produce regenerative glutamate spikes that were typical in RTT hippocampus, and virtually absent in WT ( Balakrishnan & Mironov, 2018a ; Balakrishnan & Mironov, 2018b ; Balakrishnan & Mironov, 2018 ). Glutamate spikes in WT readily emerged only after activation of metabotropic glutamate receptors (mGluR) ( Balakrishnan & Mironov, 2018 ).…”

Section: Introductionmentioning

confidence: 98%

“…To this end, we monitored the activity of hippocampal CA1 neurons using the whole-cell patch-clamp technique and measured ambient glutamate with fluorescent sensor iGluSnFr targeted to the membrane of neurons or astrocytes. As in the previous studies ( Balakrishnan & Mironov, 2018a ; Balakrishnan & Mironov, 2018b ; Balakrishnan & Mironov, 2018 ), we routinely compared the responses in slices from the wild-type (WT) mice and animals carrying the Rett Syndrome (RTT) deficiency. The rationale was to seek for possible differences in responses to

in RTT and WT to ammonia, because the Rett Syndrome has been originally attributed to hyperammonemia ( Rett, 1966 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Instant activation of TRP channels by NH4+ promotes neuronal bursting and glutamate spikes in CA1 neurons

Balakrishnan

Mironov

2020

Current Research in Physiology

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Ammonia ( ) is a by-product of cell metabolism and may elicit subcellular effects with specific physiological responses. Chronic effects have been implicated in several neurological diseases and attributed to persistent elevation in blood ammonia levels transferred to the brain. In previous studies the activities of neurons and astrocytes have been examined at ammonia concentrations an order of magnitude higher than measured in the blood. The effects developed within several minutes. Here we focused upon acute responses of neurons to ammonia and whether they may occur at much lower doses. To this end, we combined patch-clamp in CA1 neurons with glutamate imaging in hippocampal slices. Particular attention was paid to the Rett syndrome that has been originally attributed to hyperammonemia. We compared the responses in the wild-type (WT) and model Rett mice (MECP2-null, RTT) to ammonia doses from 0.3 mM on. In both preparations promptly depolarized neurons and increased the ambient glutamate. The bursting activity emerged in WT and it was augmented in RTT. Searching for subcellular mechanisms we examined possible modulation of ion channels by ammonia. We did not find any changes in HCN- and Ca 2+ currents, which substantially contribute to the bursting activity. The non-selective cation channels were markedly potentiated by ammonia. ASIC channels had a major contribution to the augmentation of neuronal activity by ammonia. Interestingly, their general blocker amiloride (100 μM) moderately excited CA1 cells akin to . In its presence subsequent ammonia effects were markedly compromised. Blockade of TRPC1 channels partially occluded effects. ASIC and TRPC1 blockers decreased the amplitude of excitatory postsynaptic currents (EPSC) and neuronal bursts, congruent with a postsynaptic location of the channels. Inhibition of TRPV1 channels potentiated the responses to . EPSC amplitudes did not change, but the frequency decreased, indicating presynaptic effects. All extracellular actions were observed at concentrations as low as 0.3 mM and the neurons reacted immediately after ammonia arrived the slice. We propose that a brief augmentation of neuronal activity by may occur either spontaneously during arousal or induced by inhalation of smelling salts.

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Entering a new era of quantifying glutamate clearance in health and disease

Brymer

Barnes

Parsons

2021

J of Neuroscience Research

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Glutamate is the brain's primary excitatory neurotransmitter and is essential for rapid excitatory synaptic neurotransmission, neuronal survival, and synaptic plasticity. Paradoxically, glutamate can also act as a toxic chemical, and enhanced glutamate-induced excitotoxicity is heavily implicated in numerous central nervous system (CNS) diseases including Alzheimer disease (AD) and Huntington disease (HD), among others (Parsons & Raymond, 2014). As glutamate is not metabolized in the extracellular space, the CNS is equipped with highly efficient excitatory amino acid transporters (EAATs) that rapidly clear extracellular glutamate following neural activity. The majority of EAATs are located on astrocytes, with lower expression

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CA1 Neurons Acquire Rett Syndrome Phenotype After Brief Activation of Glutamatergic Receptors: Specific Role of mGluR1/5

Cited by 8 publications

References 40 publications

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

A GRM7 mutation associated with developmental delay reduces mGlu7 expression and produces neurological phenotypes

Instant activation of TRP channels by NH4+ promotes neuronal bursting and glutamate spikes in CA1 neurons

Entering a new era of quantifying glutamate clearance in health and disease

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