Altered hippocampal dendritic spine maturation after hypoxia-induced seizures in neonatal rats

Mol Cell Neurosci. 2021 Jun;113:103629. doi: 10.1016/j.mcn.2021.103629. Epub 2021 May 18.

Abstract

Cognitive comorbidities often follow early-life seizures (ELS), especially in the setting of autism and other neurodevelopmental syndromes. However, there is an incomplete understanding of whether neuronal and synaptic development are concomitantly dysregulated. We have previously shown that hypoxia-induced seizures (HS) in postnatal day (P)10 rats increase acute and later-life hippocampal glutamatergic neurotransmission and spontaneous recurrent seizures, and impair cognition and behavior. As dendritic spines critically regulate synaptic function, we hypothesized that ELS can induce developmentally specific changes in dendritic spine maturation. At intervals during one month following HS in P10 rats, we assessed dendritic spine development on pyramidal neurons in the stratum radiatum of hippocampal area CA1. Compared to control rats in which spine density significantly decreased from P10 to early adulthood (P38), post-seizure rats failed to show a developmental decrease in spine density, and spines from P38 post-seizure rats appeared more immature-shaped (long, thin). In addition, compared to P38 control rats, post-seizure P38 rats expressed significantly more synaptic PSD-95, a marker of mature synapses. These changes were preceded by a transient increase in hippocampal expression of cofilin phosphorylated at Ser3, representing a decrease in cofilin activity. These results suggest that early-life seizures may impair normal dendritic spine maturation and pruning in CA1 during development, resulting in an excess of less efficient synapses, via activity-dependent modification of actin-regulating proteins such as cofilin. Given that multiple neurodevelopmental disorders show similar failures in developmental spine pruning, the current findings may represent a deficit in structural plasticity that could be a component of a mechanism leading to later-life cognitive consequences associated with early-life seizures.

Keywords: Cofilin; Development; Early-life seizures; Pruning; Structural plasticity.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Animals
  • CA1 Region, Hippocampal / growth & development
  • CA1 Region, Hippocampal / metabolism
  • CA1 Region, Hippocampal / pathology*
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology*
  • Hypoxia, Brain / complications*
  • Male
  • Rats
  • Rats, Long-Evans
  • Seizures / etiology
  • Seizures / metabolism
  • Seizures / pathology*

Substances

  • Actin Depolymerizing Factors