Environmental manipulations early in development alter seizure activity, Ih and HCN1 protein expression later in life.
Although absence epilepsy has a genetic origin, evidence from an animal model (Wistar Albino Glaxo/Rijswijk; WAG/Rij) suggests that seizures are sensitive to environmental manipulations. Here, we show that manipulations of the early rearing environment (neonatal handling, maternal deprivation) of WAG/Rij rats leads to a pronounced decrease in seizure activity later in life. Recent observations link seizure activity in WAG/Rij rats to the hyperpolarization-activated cation current (Ih) in the somatosensory cortex, the site of seizure generation. Therefore, we investigated whether the alterations in seizure activity between rats reared differently might be correlated with changes in Ih and its channel subunits hyperpolarization-activated cation channel HCN1, 2 and 4. Whole-cell recordings from layer 5 pyramidal neurons, in situ hybridization and Western blot of the somatosensory cortex revealed an increase in Ih and HCN1 in neonatal handled and maternal deprived, compared to control rats. The increase was specific to HCN1 protein expression and did not involve HCN2/4 protein expression, or mRNA expression of any of the subunits (HCN1, 2, 4). Our findings provide the first evidence that relatively mild changes in the neonatal environment have a long-term impact of absence seizures, Ih and HCN1, and suggest that an increase of Ih and HCN1 is associated with absence seizure reduction. Our findings shed new light on the role of Ih and HCN in brain functioning and development and demonstrate that genetically determined absence seizures are quite sensitive for early interventions.
Schridde
Ulrich
U
Department of Neurology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8018, USA. ulrich.schridde@yale.edu
Strauss
Ulf
U
Bräuer
Anja U
AU
van Luijtelaar
Gilles
G
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels; D004569:Electroencephalography; D004777:Environment; D004832:Epilepsy, Absence / Q000378:metabolism*; D005260:Female; D006234:Handling, Psychological; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D011247:Pregnancy; D011743:Pyrimidines / Q000378:metabolism; D011897:Random Allocation; D051381:Rats / Q000254:growth & development*; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D012640:Seizures / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000502:physiology*
D054815:Cyclic Nucleotide-Gated Cation Channels; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788