Synaptic Imbalance, Stereotypies, and Impaired Social Interactions in Mice With Altered Neuroligin 2 Expression

J Neurosci. 2008 Jun 11;28(24):6055-67. doi: 10.1523/JNEUROSCI.0032-08.2008.

Abstract

The level of excitation in the brain is kept under control through inhibitory signals mainly exerted by GABA neurons. However, the molecular machinery that regulates the balance between excitation and inhibition (E/I) remains unclear. Candidate molecules implicated in this process are neuroligin (NL) adhesion molecules, which are differentially enriched at either excitatory or inhibitory contacts. In this study, we use transgenic mouse models expressing NL1 or NL2 to examine whether enhanced expression of specific NLs results in synaptic imbalance and altered neuronal excitability and animal behavior. Our analysis reveals several abnormalities selectively manifested in transgenic mice with enhanced expression of NL2 but not NL1. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool in frontal cortex synapses and an overall reduction in the E/I ratio. The frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of transgenic NL2 mice. These animals also manifested stereotyped jumping behavior, anxiety, impaired social interactions, and enhanced incidence of spike-wave discharges, as depicted by EEG analysis in freely moving animals. These findings may provide the neural basis for E/I imbalance and altered behavior associated with neurodevelopmental disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Analysis of Variance
  • Animals
  • Anxiety / genetics*
  • Anxiety / physiopathology
  • Behavior, Animal
  • COS Cells
  • Cell Adhesion Molecules, Neuronal
  • Chlorocebus aethiops
  • Electroencephalography / methods
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / genetics
  • Inhibitory Postsynaptic Potentials / radiation effects
  • Interpersonal Relations*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission / methods
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Patch-Clamp Techniques / methods
  • Picrotoxin / pharmacology
  • Prefrontal Cortex / cytology
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / ultrastructure
  • Stereotyped Behavior / physiology*
  • Synapses / physiology*
  • Synapses / ultrastructure
  • Transfection / methods
  • Vesicular Glutamate Transport Proteins / metabolism

Substances

  • Cell Adhesion Molecules, Neuronal
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Vesicular Glutamate Transport Proteins
  • neuroligin 1
  • neuroligin 2
  • Picrotoxin
  • 6-Cyano-7-nitroquinoxaline-2,3-dione