Download Ih modulation of neocortical network activity is

Ih modulation of neocortical network activity is altered in a model of
cortical dysplasia
Asher J. Albertson and John J. Hablitz*
Department of Neurobiology, University of Alabama at Birmingham
Cortical dysplasia is commonly observed in cases of epilepsy. Epilepsies associated with
dysplasia are often resistant to anti-epileptic drug treatment. Freeze lesions during the
early post-natal period in rats have been extensively used as a model of cortical dysplasia.
These lesions reproduce many of the anatomical and electrophysiological characteristics
of human focal cortical dysplasia including a region of hyperexcitability surrounding the
malformation. Furthermore, animals with freeze-lesions have a reduced seizure
threshold. The mechanisms behind hyperexcitability in cortical dysplasia are poorly
understood. Ih is a non-specific cation current which activates upon membrane
hyperpolarization. This current is mediated by hyperpolarization activated non-specific
cation (HCN) channels. Alterations in Ih have been implicated in epilepsy. HCN
channels are predominantly present in the apical dendrites of pyramidal neurons and have
been strongly implicated in modulation of synaptic inputs. Loss of Ih leads to an increase
in intrinsic excitability while enhanced Ih reduces excitability. Additionally, the antiepileptic drug lamotrigine works via enhancement of Ih. We hypothesized that the role of
Ih in intrinsic excitability of individual cells translates to an effect on network activity
within the neocortex. We also hypothesized that this effect would be altered in the freeze
lesion model of cortical dysplasia. Using voltage sensitive dye imaging, we have shown
that Ih blockade increases the duration of cortical network activity. In contrast, Ih
enhancement with the antiepileptic drug lamotrigine decreases the spread of activity
across the cortex. Voltage sensitive dye imaging also revealed increased spread and
amplitude of activity in the area near the freeze lesion. Dysplastic cortex also showed a
reduced response to lamotrigine. These results suggest that Ih normally modulates
network activity in the neocortex. This modulation is altered in cortical dysplasia.