Age-dependent spontaneous hyperexcitability and impairment of GABAergic function in the hippocampus of mice lacking...

Patterned intrinsic network activity plays a central role in shaping immature neuronal networks into functional circuits. However, the long-lasting signals that regulate spontaneous activity of developing circuits have not been identified. Here we study the net impact of TrkB signaling on early network activity of identified neuronal populations by analyzing postnatal hippocampi from trkB null mice. Ca2+ imaging showed that pyramidal neurons of trkB-/- mice displayed a decrease in intrinsic synchronous activity in neonatal animals but an increase in juveniles. Strikingly, alterations in network activity in trkB-/- hippocampus were associated with an aberrant induction of the transcription factor Fos. In contrast to pyramidal neurons, spontaneous [Ca2+]i oscillations in trkB-/- interneurons were consistently impaired throughout postnatal development. Moreover, the number of GABAergic synapses and the expression levels of GAD65 and KCC2 were decreased in mutant hippocampi, indicating that pre- and post-synaptic GABAergic components were impaired in trkB-/- mice. Finally, the partial blockade of GABA(A) receptor in postnatal slices revealed that mutant hippocampi displayed an increased susceptibility to network hyperexcitability. These results indicate that the lack of TrkB signaling during development impairs GABAergic neurotransmission, thereby leading to an age-dependent decrease followed by an increase in the intrinsic excitability of neuronal circuits. Furthermore, the present study indicates that long-lasting TrkB signaling may contribute to the construction of CNS circuits by modulating patterns of spontaneous [Ca2+]i oscillations.