Hippocampal Heterotopia With Molecular and Electrophysiological Properties of Neocortical Neurons

Neuroscience. 2002;114(4):961-72. doi: 10.1016/s0306-4522(02)00296-8.

Abstract

Cortical malformations resulting from aberrant brain development can be associated with mental retardation, dyslexia, and intractable forms of epilepsy. Despite emerging interest in the pathology and etiology of cortical malformations, little is known about the phenotype of cells within these lesions. In utero exposure to the DNA methylating agent methylazoxymethanol acetate (MAM) during a critical stage in neurodevelopment results in animals with distinct clusters of displaced neurons in hippocampus, i.e. nodular heterotopia. Here we examined the molecular and electrophysiological properties of cells within hippocampal heterotopia using rats exposed to MAM during gestation. Molecular analysis revealed that heterotopic cells do not express mRNA markers normally found in hippocampal pyramidal cells or dentate granule cells (SCIP, Math-2, Prox-1, neuropilin-2). In contrast, Id-2 mRNA, normally abundant in Layer II-III supragranular neocortical neurons but not in CA1 pyramidal neurons, was prominently expressed in hippocampal heterotopia. Current-clamp analysis of the firing properties of heterotopic neurons revealed a striking similarity with supragranular cortical neurons. In particular, both cells were characterized by small hyperpolarizing 'sag' potentials, high input resistance values, slow spike-train afterhyperpolarizations, and the absence of a depolarizing afterpotential. Normotopic CA1 pyramidal neurons (e.g. pyramidal cells with normal lamination adjacent to a heterotopia) in the MAM brain exhibited molecular and electrophysiological properties that were nearly identical to those of age-matched CA1 pyramidal neurons from control rats. We conclude that neuronal heterotopiae in the hippocampus of MAM-exposed rats are comprised of neurons with a Layer II-III supragranular cortex phenotype. The MAM model, therefore, may serve as a useful tool in examination of the factors influencing aberrant brain development and epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Brain Diseases / pathology
  • Brain Diseases / physiopathology*
  • Cell Movement
  • Cerebral Cortex / abnormalities*
  • Cerebral Cortex / pathology
  • Choristoma / pathology
  • Choristoma / physiopathology*
  • Female
  • Gene Expression
  • Hippocampus / abnormalities*
  • Hippocampus / pathology
  • Homeodomain Proteins / genetics
  • Neuropilin-2 / genetics
  • Octamer Transcription Factor-6
  • Patch-Clamp Techniques
  • Pregnancy
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Neurod6 protein, rat
  • Neuropilin-2
  • Pou3f1 protein, rat
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Proteins
  • prospero-related homeobox 1 protein
  • Octamer Transcription Factor-6