Cortical synaptic NMDA receptor deficits in α7 nicotinic acetylcholine receptor gene deletion models: implications for neuropsychiatric diseases

Neurobiol Dis. 2014 Mar;63:129-40. doi: 10.1016/j.nbd.2013.11.021. Epub 2013 Dec 8.

Abstract

Microdeletion of the human CHRNA7 gene (α7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-d-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with α7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that α7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in mouse cortex. α7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking α7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of α7 nAChR null mice. Moreover, d-serine responsive synaptic NMDAR-mediated currents and levels of the d-serine synthetic enzyme serine racemase were both reduced in α7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in α7 nAChR gene deletion models of cortical dysfunction, thereby implicating α7 nAChR-mediated control of synaptic NMDARs and serine racemase/d-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7.

Keywords: Cortex; Extrasynaptic NMDA receptor; Glutamatergic synaptic deficits; N-methyl-d-aspartate receptor; NMDAR; Neuropsychiatric diseases; SR; Schizophrenia; Serine racemase; Synaptic NMDA receptor; VGLUT1; WT; d-serine; nAChR; nicotinic acetylcholine receptor; serine racemase; vesicular glutamate transporter 1; wild-type; α7 nAChR null; α7 nicotinic acetylcholine receptor; α7-KO.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Disks Large Homolog 4 Protein
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics*
  • Guanylate Kinases / metabolism
  • In Vitro Techniques
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / physiology*
  • Pregnancy
  • Receptors, N-Methyl-D-Aspartate / deficiency*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Synapses / metabolism*
  • Vesicular Glutamate Transport Protein 1 / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor / deficiency*
  • alpha7 Nicotinic Acetylcholine Receptor / genetics

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Membrane Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Vesicular Glutamate Transport Protein 1
  • alpha7 Nicotinic Acetylcholine Receptor
  • Guanylate Kinases