We have investigated the role of
somatostatin receptor subtypes sst2 and sst4 in limbic
seizures and
glutamate-mediated neurotransmission in mouse hippocampus. As compared to wild-type littermates, homozygous mice lacking sst2 receptors showed a 52% reduction in EEG ictal activity induced by intrahippocampal injection of 30 ng
kainic acid (P < 0.05). The number of behavioural
tonic-clonic seizures was reduced by 50% (P < 0.01) and the time to onset of
seizures was doubled on average (P < 0.05). Seizure-associated neurodegeneration was found in the injected hippocampus (CA1, CA3 and hilar interneurons) and sporadically in the ipsilateral latero-dorsal thalamus. This occurred to a similar extent in wild-type and sst2 knock-out mice. Intrahippocampal injection of three selective sst2 receptor agonists in wild-type mice (
Octreotide,
BIM 23120 and
L-779976, 1.5-6.0 nmol) did not affect
kainate seizures while the same compounds significantly reduced
seizures in rats. L-803087 (5 nmol), a selective
sst4 receptor agonist, doubled seizure activity in wild-type mice on average. Interestingly, this effect was blocked by 3 nmol
octreotide. It was determined, in both radioligand binding and cAMP accumulation, that
octreotide had no direct agonist or antagonist action at mouse sst4 receptors expressed in CCl39 cells, up to micromolar concentrations. In hippocampal slices from wild-type mice,
octreotide (2 micro m) did not modify
AMPA-mediated synaptic responses while facilitation occurred with L-803087 (2 micro m). Similarly to what was observed in
seizures, the effect of L-803087 was reduced by
octreotide. In hippocampal slices from sst2 knock-out mice, both
octreotide and L-803087 were ineffective on synaptic responses. Our findings show that, unlike in rats, sst2 receptors in mice do not mediate
anticonvulsant effects. Moreover, stimulation of sst4 receptors in the hippocampus of wild-type mice induced excitatory effects which appeared to depend on the presence of sst2 subtypes, suggesting these receptors are functionally coupled.