Age-dependent regulation of synaptic connections by dopamine D2 receptors

Nat Neurosci. 2013 Nov;16(11):1627-36. doi: 10.1038/nn.3542. Epub 2013 Oct 13.


Dopamine D2 receptors (D2R) are G protein-coupled receptors that modulate synaptic transmission and are important for various brain functions, including learning and working memory. Abnormal D2R signaling has been implicated in psychiatric disorders such as schizophrenia. Here we report a new function of D2R in dendritic spine morphogenesis. Activation of D2R reduced spine number via GluN2B- and cAMP-dependent mechanisms in mice. Notably, this regulation occurred only during adolescence. During this period, D2R overactivation caused by mutations in the schizophrenia risk gene Dtnbp1 led to spine deficiency, dysconnectivity in the entorhinal-hippocampal circuit and impairment of spatial working memory. Notably, these defects could be ameliorated by D2R blockers administered during adolescence. Our findings suggest an age-dependent function of D2R in spine development, provide evidence that D2R dysfunction during adolescence impairs neuronal circuits and working memory, and indicate that adolescent interventions to prevent aberrant D2R activity protect against cognitive impairment.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Age Factors
  • Aging*
  • Anesthetics, Local / pharmacology
  • Animals
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Dark Adaptation / drug effects
  • Dark Adaptation / physiology
  • Dopamine Agents / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • Gene Expression Regulation / genetics
  • Hippocampus / cytology
  • In Vitro Techniques
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neurons / cytology*
  • Neurons / drug effects
  • Rats
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D2 / physiology*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / physiology*
  • Time Factors


  • Anesthetics, Local
  • Dopamine Agents
  • Excitatory Amino Acid Antagonists
  • NR2B NMDA receptor
  • Receptors, Dopamine D2
  • Receptors, N-Methyl-D-Aspartate
  • 6-Cyano-7-nitroquinoxaline-2,3-dione