Related Experiment Video

Updated: Nov 24, 2025

Strategies for Assessing Autistic-Like Behaviors in Mice
07:38

Strategies for Assessing Autistic-Like Behaviors in Mice

Published on: September 20, 2024

1.8K

Persistently Elevated mTOR Complex 1-S6 Kinase 1 Disrupts DARPP-32-Dependent D1 Dopamine Receptor Signaling and

Raozhou Lin1, Lisa N Learman1, Chan-Hyun Na2

  • 1Solomon Snyder Department of Neuroscience, School of Medicine, Johns Hopkins University, Baltimore, Maryland.

Biological Psychiatry
|December 23, 2020
PubMed
Abstract

Insights

Aberrant mTORC1 signaling in the brain disrupts dopamine D1 receptor function by blocking DARPP-32, impacting gene expression, neural plasticity, and behavior in neuropsychiatric disorders.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • Mechanistic target of rapamycin complex 1 (mTORC1) is crucial for cell function but its aberrant activation in the brain is linked to neuropsychiatric disorders.
  • The molecular basis for cognitive and neuropsychiatric symptoms associated with mTORC1 dysregulation remains unclear.

Purpose of the Study:

  • To investigate the impact of persistently elevated mTORC1 signaling on dopamine D1 receptor (D1R) signaling pathways.
  • To elucidate the molecular mechanisms underlying behavioral and cognitive deficits in neurological diseases characterized by mTORC1 hyperactivity.

Main Methods:

  • Utilized transgenic models with elevated Rheb expression to mimic persistent mTORC1 activation.
  • Employed phosphoproteomics, biochemistry, immunohistochemistry, electrophysiology, and behavioral analyses to study D1R signaling.
  • Confirmed findings in D1R neurons using D1-Cre driver lines.

Main Results:

  • Persistently elevated mTORC1 signaling inhibits canonical D1R signaling dependent on DARPP-32.
  • mTORC1's downstream effector, S6K1, phosphorylates and activates DARPP-32, leading to occlusion of D1R signaling.
  • Blocked D1R-mediated gene expression, corticostriatal plasticity, and behavioral responses like sociability.
  • Identified candidate biomarkers of mTORC1-DARPP-32 pathway occlusion in human disease subjects.

Conclusions:

  • The mTORC1-S6K1 pathway intersects with D1R signaling, providing a molecular explanation for behavioral symptoms in neuropsychiatric diseases.
  • This interaction offers a framework for understanding how pathological mTORC1 activation contributes to cognitive dysfunction and neurological disease.
Keywords:
D(1) dopamine receptorDARPP-32Immediate early geneS6K1Social behaviormTORC1

More Related Videos

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia10:41

Implantation of Osmotic Pumps and Induction of Stress to Establish a Symptomatic, Pharmacological Mouse Model for DYT/PARK-ATP1A3 Dystonia

Published on: September 12, 2020

7.7K
Developing a Rat Model for Bipolar Disorder04:42

Developing a Rat Model for Bipolar Disorder

Published on: May 2, 2025

930

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.8K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.1K
Drugs Affecting Neurotransmitter Synthesis01:29

Drugs Affecting Neurotransmitter Synthesis

Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase,...
1.9K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.3K
Parkinson's Disease: Treatment01:24

Parkinson's Disease: Treatment

Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
765
Desensitization and Tachyphylaxis01:20

Desensitization and Tachyphylaxis

Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
2.7K