Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal

Neuroscience. 2011 Apr 28;180:314-21. doi: 10.1016/j.neuroscience.2011.01.061. Epub 2011 Feb 4.

Abstract

Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X-linked gene, MECP2, has a phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype. One of the consequences of MeCP2 absence in the brain is altered functional and structural plasticity. We aimed to characterize synaptic effects related to plasticity in the hippocampus further and establish whether plasticity defects are amenable to pharmacological reversal. Using male mice in which Mecp2 expression was prevented by a stop cassette, we assessed synaptic plasticity in area CA1 at different phenotypic stages, scoring the mice weekly for overt RTT-like signs. Strongly symptomatic Mecp2(stop/y) mice displayed reduced long-term potentiation (LTP, 40.2±1.6% of wild-type), post-tetanic potentiation (PTP, 45±18.8% of wild-type) and paired-pulse facilitation (PPF, 78±0.1% of wild type) (all P<0.05), the impairment increasing with symptom severity score. These plasticity impairments were absent in presymptomatic mice. Repeated high frequency stimulation revealed pronounced LTP saturation in symptomatic Mecp2(stop/y) mice, suggesting an LTP 'ceiling' effect. Bath application of the weak NMDA receptor blocker memantine (1 μM) resulted in partial restoration of a short-term plasticity component. These data support that idea that progressive functional synaptic impairment is a key feature in the RTT brain and demonstrate the potential for the pharmacological restoration of plasticity function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Brain / drug effects*
  • Brain / physiopathology
  • Disease Models, Animal
  • Dopamine Agents / pharmacology*
  • Immunohistochemistry
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / physiology
  • Male
  • Memantine / pharmacology*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mice
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Patch-Clamp Techniques
  • Rett Syndrome / genetics
  • Rett Syndrome / physiopathology*

Substances

  • Dopamine Agents
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Memantine