4-AMINOPYRIDINE-INDUCED SPREADING DEPRESSION EPISODES IN IMMATURE HIPPOCAMPUS - DEVELOPMENTAL AND PHARMACOLOGICAL CHARACTERISTICS

Spontaneous spreading depression episodes were studied in CAI and CA3 areas of immature hippocampal slices (two to 30 days postnatally) duri ng 4-aminopyridine (50 muM) perfusion. Spreading depression occurred i n the CA3 area of 34% of all slices tested (two to 30 days postnatally ). The duration and frequency of the spreading depression field potent ials changed with development. In the CA3 area, their duration decreas ed from 169 +/- 22 s (n = 17, postnatal days two to 10) to 55 +/- 7 s (n = 10, postnatal days 21-30), their rate of occurrence increased fro m four episodes per hour (0.0011 +/- 0.0001 Hz, n = 11, postnatal days two to 10) to 6.5 episodes per hour (0.0018 +/- 0.0003 Hz, n = 8, pos tnatal days 21-30), while their amplitude remained stable (10-30 mV). Spreading depression d.c. potential shift originated closer to CA1 tha n CA3. Furthermore, spreading depression field potentials had greater magnitude (amplitude and duration) in CAI. Spreading depressions were reversibly blocked by the N-methyl-D-aspartate receptor antagonist 3-( 2-carboxy-piperazine-4-yl)-propyl-1-phosphonate (CPP, 1-5 muM, n = 15) , but were not affected by 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX , 2-5 mum, n = 11), which is a non-N-methyl-D-aspartate receptor antag onist. The GABA(A) receptor antagonist bicuculline methiodide (3-10 mu M) initially favored and then blocked spreading depression in 79% of t he slices tested (n = 16). In addition, bicuculline impaired spreading depression propagation from CAI to CA3. 4-Aminopyridine also induced the appearance of other types of spontaneous activity, such as ictal a nd interictal-like epileptiform discharges. The effects of -(2-carboxy -piperazine-4-yl)-propyl-1-phosphonate, 6-cyano-7-nitro-quinoxaline-2, 3-dione and bicuculline on epileptiform activity were opposite to thos e on spreading depression. Our findings demonstrate that spreading dep ression can occur as early as two days postnatally and that the charac teristics of this phenomenon change with maturation. These results als o indicate that 4-aminopyridine-induced spreading depression episodes and epileptiform activity are mediated by the activation of different types of excitatory amino acid receptors. Finally, spreading depressio n is influenced by blockade of the GABA(A) receptor.