Abstracts

Rationale: Infantile spasms is an early-onset severe epileptic encephalopathy. Studies suggest that disruption of cortical networks may be important in the pathogenesis of this seizure disorder although the underlying mechanisms remain unclear. In this regard, ictal and interictal high frequency oscillations have been observed in our rat model as well as human patients and are decreased by medications used in the treatment of infantile spasms. Here we hypothesize that cortical network excitability is altered in infantile spasms and this is reflected as increases in local circuit-based high frequency oscillations and changes in cortical Up states.Methods: Spasms were induced by a unilateral chronic infusion of 12 µM tetrodotoxin into rat somatosensory cortex beginning on postnatal day (P) 11. The presence of spasms was verified by observing behavioral spasms between P16 and P21. Local field potentials and multi-unit activity were recorded from somatosensory cortex of acute brain slices taken from animals between P21 and P28.Results: We found that high frequency oscillations occurred more frequently in slices from rats with spasms (8.0 per hour) than in control animals (1.9 per hour; n=4; p<0.05). Furthermore high frequency oscillations in epileptic animals were significantly longer in duration (84.6 ms) compared to controls (23.3 ms; p<0.05). Cortical Up states occurred less frequently in epileptic animals (average rate of occurrence: 0.073 Hz, n= 14) compared to control animals (0.144 Hz; n=15; p<0.05). The cortical Up states were also significantly smaller in amplitude in animals with spasms (-42.3 µV) compared to controls (-87.7 µV; p<0.05). We also observed that cortical Up states and high frequency oscillations can occur independently and simultaneously suggesting they originate from different cortical networks.Conclusions: Results suggest that the cortical networks generating Up states are disrupted in our model of infantile spasms. Additionally there is upregulation of a distinct cortical network that produces longer and more frequent high frequency oscillations. The latter are reminiscent of fast EEG oscillations recorded from human patients with infantile spasms. Further studies are needed to elucidate the components of the cortical networks and mechanisms responsible for these alterations in network excitability.