Control of spike transfer at hippocampal mossy fiber synapses in vivo by GABAA and GABAB receptor mediated inhibition.

Despite extensive studies in hippocampal slices and incentive from computational theories, the synaptic mechanisms underlying information transfer at mossy fiber (mf) connections between the dentate gyrus (DG) and CA3 neurons in vivo are still elusive. Here we used an optogenetic approach in mice to selectively target and control the activity of DG granule cells (GCs) while performing whole cell and juxtacellular recordings of CA3 neurons in vivo In CA3 pyramidal cells (PCs), mf-CA3 synaptic responses consisted predominantly of an inhibitory postsynaptic potential (IPSP) at low stimulation frequency (0.05 Hz). Upon increasing the frequency of stimulation, a biphasic response was observed consisting in a brief mf-EPSPs followed by an inhibitory response lasting on the order of 100 ms. Spike transfer at DG-CA3 interneurons recorded in the juxtacellular mode was efficient at low presynaptic stimulation frequency, and appeared insensitive to increased frequency of GCs activity. Overall this resulted in a robust and slow feedforward inhibition of spike transfer at mf-CA3 pyramidal cell synapses. Short-term plasticity of excitatory postsynaptic potentials with increasing frequency of presynaptic activity allowed overcoming inhibition to reach spike discharge in CA3 PCs. Whereas the activation of GABAA receptors was responsible for the direct inhibition of light-evoked spike responses, the slow inhibition of spiking activity required the activation of GABAB receptors in CA3 PCs. The slow inhibitory response defined an optimum frequency of presynaptic activity for spike transfer around 10 Hz. Altogether these properties define the temporal rules for efficient information transfer at DG-CA3 synaptic connections in the intact circuit.

SIGNIFICANCE STATEMENT: Activity-dependent changes in synaptic strength constitute a basic mechanism for memory. Synapses from the dentate gyrus (DG) to the CA3 area of the hippocampus are distinctive for their prominent short-term plasticity, as studied in slices. Plasticity of DG-CA3 connections may assist in the encoding of precise memory in the CA3 network. Here we characterize DG-CA3 synaptic transmission in vivo using targeted optogenetic activation of DG granule cells while recording in whole-cell patch-clamp and juxtacellular configuration from CA3 pyramidal cells and interneurons. We show that in vivo, short term plasticity of excitatory inputs to CA3 pyramidal cells combines with robust feedforward inhibition mediated by both GABAA and GABAB receptors to control the efficacy and temporal rules for information transfer at DG-CA3 connections.