Histamine H3 receptor activation decreases kainate-induced hippocampal gamma oscillations in vitro by action potential desynchronization in pyramidal neurons

Abstract

The study of rhythmic electrical activity in slice preparations has generated important insights into neural network function. While the synaptic mechanisms involved in the generation of in vitro network oscillations have been studied widely, little is known about the modulatory influence exerted on rhythmic activity in neuronal networks by neuropeptides and biogenic amines. Gamma oscillations play an important role in cognitive processes and are altered or disrupted in disorders such as Alzheimer's disease (AD) and schizophrenia. Given the importance of gamma oscillations for learning, memory and cognition processes as well as the recent interest in histamine H(3) receptors in the development of pro-cognitive drugs to treat disorders such as AD and schizophrenia, it is relevant to study the impact of histaminergic mechanisms on network gamma oscillations. Here we show for the first time a modulation of gamma oscillation by histaminergic mechanisms. Selective activation of the H(3) receptor by R-alpha-methylhistamine significantly reduces the power of kainate-induced gamma oscillations, but not carbachol-induced gamma oscillations, in the rat hippocampal slice preparation without affecting oscillation frequency. This effect is neither caused by a decrease in excitatory or inhibitory postsynaptic currents, nor a decrease in cellular excitability. Instead, we find that the decrease in oscillation power following H(3) receptor activation results from a desynchronization of pyramidal neuron action potential firing with regard to the local field potential oscillation cycle. Our data provide a possible mechanism of action for histamine in regulating gamma oscillations in the hippocampal network.

Figure 1. H₃ receptor activation decreases power of kainate- but not carbachol-induced gamma oscillations

A, kainate-induced (100 nm) gamma oscillations recorded in stratum pyramidale of CA3 are reduced 5 min after application of 100 nm RAMH. B, power spectra of the respective traces in A. C, results summary of H₃ receptor agonists and antagonist action. The oscillation power after all treatments was normalized to the power recorded after 20 min kainate application.

Figure 2. Synaptic and cellular currents in CA3 pyramidal cells are unaffected by H₃ receptor activation

A, EPSCs were recorded in standard ACSF in the absence of drugs, after kainate application, and activation of H₃ receptors. Activation of kainate receptors (middle trace) shows the strong increase in number and amplitude of EPSCs typical during gamma oscillations. Activation of H₃ receptors leaves EPSCs unaffected. Summary histogram is below. B, IPSCs were recorded in standard ACSF in the absence of drugs, after kainate application, and activation of H₃ receptors. Activation of kainate receptors (middle trace) shows the strong increase in number and amplitude of IPSCs typical during gamma oscillations. Activation of H₃ receptors leaves IPSCs unaffected. GABA_A receptor block (lowest trace) removes the PSCs observed before and confirms their inhibitory nature. Summary histogram is below. C, example trace of cellular current recording (left; V_h=−60 mV). Observe a slowly developing inward current in response to kainate but no additional response to RAMH. The summary diagram (right) quantifies the cellular current experiments.

Figure 3. H₃ receptor activation desynchronizes action potential firing in CA3 pyramidal cells

A, concomitant recordings of cellular action potential firing and extracellular gamma oscillations. Lower traces are excerpts from the upper traces at increased temporal resolution. H₃ receptor activation results in a decreased gamma oscillation amplitude. B, the average oscillation cycles of the traces in A are shown in the diagrams. The histograms show 2 ms bin counts of action potentials occurring during the oscillation cycles. The detected number of cycles are roughly the same before and after RAMH. Fitted to the histograms are 3rd order polynomial functions (see Methods). In kainate-only conditions action potentials show a clear synchronization and phase preference. H₃ receptor activation causes action potential firing to become desynchronized, which is reflected in the flatter profile of the histogram and a lower ‘a’ coefficient. C, summary diagram showing the ‘a’ coefficients before and after H₃ receptor activation.