Smad3 deficiency inhibits dentate gyrus LTP by enhancing GABAA neurotransmission

J Neurochem. 2016 Apr;137(2):190-9. doi: 10.1111/jnc.13558. Epub 2016 Feb 18.

Abstract

Transforming growth factor-β signaling through intracellular Smad3 has been implicated in Parkinson's disease (PD) and it fulfills an important role in the neurogenesis and synaptic plasticity that occurs in the adult dentate gyrus (DG). The long-term potentiation (LTP) induced in the DG by high-frequency stimulation of the medial perforant pathway is abolished in the DG of Smad3-deficient mice, but not in the CA1 hippocampal region. Here, we show that NMDA- and AMPA-type glutamate receptors do not participate in the inhibition of LTP associated with Smad3 deficiency. Moreover, there is no difference in the hippocampal GAD65 and GAD67 content, suggesting that GABA biosynthesis remains unaffected. Increased conductance and higher action potential firing thresholds were evident in intracellular recordings of granule cells from Smad3 deficient mice. Interestingly, phasic and tonic GABAA receptor (GABAA R)-mediated neurotransmission is enhanced in the DG of Smad3-deficient mice, and LTP induction can be rescued by inhibiting GABAA R with picrotoxin. Hence, Smad3 signaling in the DG appears to be necessary to induce LTP by regulating GABAA neurotransmission, suggesting a central role of this intracellular signaling pathway in the hippocampal brain plasticity related to learning and memory. Smad3 deficient mice represent a new and interesting model of Parkinson's disease, displaying hippocampal dysfunctions that include decreased neurogenesis and the failure to induce LTP in the dentate gyrus. Here we show that Smad3 deficiency inhibits LTP induction by enhancing phasic and tonic GABAA receptor-mediated neurotransmission, while LTP induction can be rescued with a GABAA receptor antagonist. Alteration of GABA neurotransmission is thought to produce hippocampal cognitive dysfunction in Down's syndrome or Alzheimer's disease, and here we provide new insights into the hippocampal changes in an animal model of Parkinson's disease.

Keywords: GABA; LTP; Parkinson's disease; Smad3; TGF-beta; hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Biophysics
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / physiology*
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • GABA Antagonists / pharmacology
  • Glutamate Decarboxylase / metabolism
  • In Vitro Techniques
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / genetics*
  • Mice
  • Mice, Knockout
  • Nerve Net / physiology
  • Picrotoxin / pharmacology
  • Smad3 Protein / deficiency*
  • Smad3 Protein / genetics
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*

Substances

  • GABA Antagonists
  • Smad3 Protein
  • Smad3 protein, mouse
  • Picrotoxin
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • glutamate decarboxylase 2