Cannabinoids attenuate hippocampal gamma oscillations by suppressing excitatory synaptic input onto CA3 pyramidal neurons and fast spiking basket cells

Non-Technical Summary  Administration of cannabinoids can impair several cognitive functions, including memory by altering synchronous activities in cortical networks. We show that the gamma frequency (40 Hz) oscillations in hippocampal slices, that are prominent oscillations in electroencephalogram during awake states in vivo, are reduced by cannabinoids. This effect can be explained by the suppression of the excitatory synaptic transmission onto fast spiking basket cells, GABAergic cells that are key players in oscillogenesis. The reduced excitatory drive onto these interneurons leads to a reduction in neuronal firing frequency and precision, and thus to smaller field potentials. Our data further our understanding of the synaptic mechanisms of how cannabinoids alter neuronal operation. Abstract  CB1 cannabinoid receptor (CB1R) activation by exogenous ligands can impair memory processes, which critically depend on synchronous neuronal activities that are temporarily structured by oscillations. In this study, we aimed to reveal the mechanisms underlying the cannabinoid-induced decrease in gamma oscillations. We first verified that cannabinoids (CP55,940 and WIN55,212-2) readily suppressed carbachol-induced gamma oscillations in the CA3 region of hippocampal slices via activation of CB1Rs. The cannabinoid-induced decrease in the peak power of oscillations was accompanied by reduced and less precise firing activity in CA3 pyramidal cells and fast spiking basket cells. By examining the cannabinoid sensitivity of synaptic inputs we found that the amplitude of evoked excitatory postsynaptic currents was significantly suppressed upon CB1R activation in both CA3 pyramidal cells and fast spiking basket cells. In contrast, evoked inhibitory postsynaptic currents in CA3 pyramidal cells were unaltered. Furthermore, we observed that a CB1R agonist-induced decrease in the oscillation power at the beginning of the drug application was accompanied primarily by the reduced discharge of fast spiking basket cells, while pyramidal cell firing was unaltered. This result implies that the dampening of cholinergically induced gamma oscillations in the hippocampus by cannabinoids can be explained by a reduced excitatory input predominantly onto fast spiking basket cells, which leads to a reduction in neuronal firing frequency and precision, and thus to smaller field potentials. In addition, we uncovered that the spontaneously occurring sharp wave-ripple activities in hippocampal slices could also be suppressed by CB1R activation suggesting that cannabinoids profoundly reduce the intrinsically generated oscillatory activities at distinct frequencies in CA3 networks by reducing synaptic neurotransmission.