Inhibitory Postsynaptic Potentials Participate in Intracellular and Extracellular Theta Rhythms in the Hippocampus: A Personal Narrative

The hypothesis that the hippocampal theta rhythm consists of inhibitory postsynaptic potentials (IPSPs) was critical for understanding the theta rhythm. The dominant views in the early 1980s were that intracellularly recorded theta consisted of excitatory postsynaptic potentials (EPSPs) with little participation by IPSPs, and that IPSPs generated a closed monopolar field in the hippocampus. I (Leung) conceived of a new model for generation of the hippocampal theta rhythm, with theta-rhythmic IPSPs as an essential component, and thus sought to reinvestigate the relation between theta and IPSPs quantitatively with intracellular and extracellular recordings. The intracellular recordings were performed by Leung and Yim in the laboratory of Kris Krnjević at McGill University. Using protocols of passing steady-state holding currents and injection of chloride ions, the intracellular theta and IPSP in a CA1 neuron typically showed the same reversal potential and correlated change in amplitude. Low-intensity stimulation of the alveus evoked an antidromic action potential in CA1 neurons, identifying them as pyramidal cells with output axons in the alveus, which then activated a feedback IPSP with almost no excitatory component. Theta-rhythmic somatic inhibition, together with phase-shifted theta-rhythmic distal apical dendritic excitation were proposed as the two dipoles that generate a gradual extracellular theta phase shift in the CA1 apical dendritic layer. The distal apical excitation driven by the entorhinal cortex was proposed to be atropine-resistant and dominated during walking in rats. Other than serving a conventional role in limiting excitation, rhythmic proximal inhibition and distal dendritic excitation provide varying phasic modulation along the soma-dendritic axis of pyramidal cells, resulting in theta phase-dependent synaptic plasticity and gamma oscillations, which are likely involved in cognitive processing.