A Cellular Mechanism for Graded Persistent Activity in a Model Neuron and Its Implications in Working Memory

Working memory represents the ability of the brain to hold information for relatively short periods of time. Working memory is believed mediated by persistent neuronal firing. A broadly accepted hypothesis is that persistent activity is generated by reverberating synaptic input. However, single cortical neurons capable of showing persistent firing were recently reported. In this modeling study, we propose a cellular mechanism to generate persistent firing of multiple firing rates in single neurons. In the proposed mechanism, bistable concentrations of inositol 1,4,5-trisphosphate (IP₃) and Ca²⁺ is achieved by IP₃ formation and IP₃-induced Ca²⁺ release from stores in multiple subcellular domains. A postsynaptic firing rate-dependent switching of these bistable elements can demonstrate graded persistent firing of the rat entorhinal neurons. Such a firing rate-dependent switching may be extended to a variety of intracellular Ca²⁺ signaling cascades.