Developmental molecular and functional cerebellar alterations induced by PCP4/PEP19 overexpression: implications for Down syndrome

Neurobiol Dis. 2014 Mar:63:92-106. doi: 10.1016/j.nbd.2013.11.016. Epub 2013 Nov 28.

Abstract

PCP4/PEP19 is a modulator of Ca(2+)-CaM signaling. In the brain, it is expressed in a very specific pattern in postmitotic neurons. In particular, Pcp4 is highly expressed in the Purkinje cell, the sole output neuron of the cerebellum. PCP4, located on human chromosome 21, is present in three copies in individuals with Down syndrome (DS). In a previous study using a transgenic mouse model (TgPCP4) to evaluate the consequences of 3 copies of this gene, we found that PCP4 overexpression induces precocious neuronal differentiation during mouse embryogenesis. Here, we report combined analyses of the cerebellum at postnatal stages (P14 and adult) in which we identified age-related molecular, electrophysiological, and behavioral alterations in the TgPCP4 mouse. While Pcp4 overexpression at P14 induces an earlier neuronal maturation, at adult stage it induces increase in cerebellar CaMK2alpha and in cerebellar LTD, as well as learning impairments. We therefore propose that PCP4 contributes significantly to the development of Down syndrome phenotypes through molecular and functional changes.

Keywords: Cerebellum; Down syndrome; Learning; Pcp4; Transgenic mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cerebellum / cytology
  • Cerebellum / growth & development*
  • Cerebellum / metabolism*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Humans
  • In Vitro Techniques
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / genetics
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Neurons / physiology
  • Psychomotor Performance / drug effects
  • Psychomotor Performance / physiology
  • Quinoxalines / pharmacology
  • Reaction Time / drug effects
  • Reaction Time / genetics
  • Recognition, Psychology / drug effects
  • Recognition, Psychology / physiology
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Valine / analogs & derivatives
  • Valine / pharmacology

Substances

  • Excitatory Amino Acid Antagonists
  • Nerve Tissue Proteins
  • Quinoxalines
  • Sodium Channel Blockers
  • PCP4 protein, human
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Tetrodotoxin
  • 2-amino-5-phosphopentanoic acid
  • Valine