Compared to controls, conditional Erbb4 mutants exhibited a marked increased in oscillatory power in the resting-state ( Figures 5B and 5C). Frequent bursts of high-frequency oscillations were observed in the DG, which often correlated with simultaneous increases in oscillatory power in the CA1 region and, occasionally, the overlying neocortex ( Figures 5B and 5C). Consistently, DG-CA1 coherence increased significantly in conditional Erbb4 mutants, especially at relatively high frequencies ( Figure 5D). ERK inhibitor Closer inspection of these resting-state recordings revealed the presence of spontaneous and fully developed field population spikes in the DG closely resembling field potentials
evoked by perforant path stimulation ( Figure 5E). This finding strongly suggests the presence of synchronous activity bursts already in the entorhinal cortex, a region in which we also found deficits of interneuron synapses in conditional Erbb4 mutant mice BIBW2992 price ( Figure 2I). To further investigate neuronal synchrony in the hippocampus, we measured the input-output function in the trisynaptic circuit (DG → CA3 → CA1) by correlating the excitatory postsynaptic potential (EPSP) in the DG in response to perforant path stimulation (∼2 ms delay) and the population spikes recorded in CA1 (∼8 ms
delay). We observed that the polysynaptic propagation of activity in the hippocampal formation is largely facilitated in conditional Erbb4 mutant mice ( Figures 5E, arrows, and 5F). These observations were replicated in ketamine-anesthetized conditional Erbb4 mutant
mice ( Figures S5A–S5E), which revealed that the enhanced oscillatory power observed in mice lacking ErbB4 was not directly related to a particular anesthetic compound. In some cases, however, we observed that ketamine led to epileptic hypersynchrony in conditional Erbb4 mutants (n = 3 out of six mice, data not shown), a phenomenon that was never observed in ketamine-anesthetized controls or in urethane-anesthetized control or Erbb4 mutant mice. As ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, these results suggested also that NMDA receptor blockage enhances the physiological disturbances caused by the loss of ErbB4 in fast-spiking interneurons. We observed a sustained elevation in relative power for all frequencies above 4 Hz in the CA1 area of conditional Erbb4 mutants compared to controls ( Figure 5G). This increase was significant for the theta, alpha, beta, and gamma bands ( Figures 5H) and was particularly perceptible with wavelet analyses ( Figures 5I and 5J). The dramatic alteration of hippocampal rhythms was also evident in the CA1 area of ketamine-anesthetized Erbb4 mutants ( Figures S5F–S5I) and in the DG independently of the anesthetic compound used in the experiments ( Figure S6).