Synaptic Basis of Cortical Persistent Activity: the Importance of NMDA Receptors to Working Memory

By Xiao-Jing Wang. 1999

Delay-period activity of prefrontal cortical cells, the neural hallmark of working memory, is generally assumed to be sustained by reverberating synaptic excitation in the prefrontal cortical circuit. Previous model studies of working memory emphasized the high efficacy of recurrent synapses, but did not investigate the role of temporal synaptic dynamics. In this theoretical work, I show that biophysical properties of cortical synaptic transmission are important to the generation and stabilization of a network persistent state. This is especially the case when negative feedback mechanisms (such as spike-frequency adaptation, feedback shunting inhibition, and short-term depression of recurrent excitatory synapses) are included so that the neural firing rates are controlled within a physiological range (10–50 Hz), in spite of the exuberant recurrent excitation. Moreover, it is found that, to achieve a stable persistent state, recurrent excitatory synapses must be dominated by a slow component. If neuronal firings are asynchronous, the synaptic decay time constant needs to be comparable to that of the negative feedback; whereas in the case of partially synchronous dynamics, it needs to be comparable to a typical interspike interval (or oscillation period). Slow synaptic current kinetics also leads to the saturation of synaptic drive at high firing frequencies that contributes to rate control in a persistent state. For these reasons the slow NMDA receptor-mediated synaptic transmission is likely required for sustaining persistent network activity at low firing rates. This result suggests a critical role of the NMDA receptor channels in normal working memory function of the prefrontal cortex.

Subfields: Neuroscience

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Citations in the corpus

Neural Turing Machines (2014, background): “Modeling studies of working memory range from those that consider how biophysical circuits could implement persistent neuronal ﬁring (Wang, 1999) to those that try to solve explicit tasks (Hazy et al., 2006) (Dayan, 2008) (Eliasmith, 2013).”
The computational role of dopamine D1 receptors in working memory (2002, background): “NMDA conductances, which might contribute more than 60% of the total charge delivered by excitatory synapses (Spruston, Jonas, & Sakmann, 1995), due to their long offset time constant helped to provide the sustained synaptic drive required to maintain persistent activity at reasonable firing rates (”
Synaptic and spiking dynamics underlying reward reversal in the orbitofrontal cortex. (2004, background): “As was noted by Lisman et al. (1998), Wang (1999) and Brunel and Wang (2001), the recurrent excitation was assumed to be largely mediated by the NMDA receptors, in order to provide more robust persistent activity during the short-term memory related delay period; and the amplitude of recurrent…”
Interactions between frontal cortex and basal ganglia in working memory: A computational model (2001, methodology): “Other prefrontalbased models that were discussed earlier incorporate intrinsic bistability, as in our model (Durstewitz et al., 1999; Durstewitz et al., 2000a; Fellous et al., 1998; Wang, 1999 ), but these models lack explicit gating circuitry as implemented by the basal ganglia in our model.”
Synaptic Dynamics in Analog VLSI (2007, background): “Furthermore, the NMDA’s synapse stabilizing role, hypothesized by computational studies within the context of working memory (Wang, 1999), could be useful for stabilizing persistent activity of recurrent VLSI networks of spiking neurons.”
The principal features and mechanisms of dopamine modulation in the prefrontal cortex. (2004, background): “This persistent activity is the result of a complex interplay of a variety of ionic and synaptic currents, but at least in reduced systems, depend strongly on NMDA and GABA currents (Seamans et al., 2003; Durstewitz et al., 2000b; Wang, 1999).”
Towards an executive without a homunculus: computational models of the prefrontal cortex/basal ganglia system (2007, background): “…previously noted, much evidence supports the role of the PFC in active maintenance during working memory tasks and for the existence of at least two mechanisms (recurrent connectivity and bistability) that could support it (e.g. Zipser 1991; Fellous et al. 1998; Wang 1999; Durstewitz et al. 2000).”
Dopamine and Cognitive Control in Prefrontal Cortex. (2019, background): “…networks show two stable states: a spontaneous, low-activity state dominated by inhibitory currents, and a persistent, high-activity state of subsets of pyramidal cells with strong recurrent excitatory connections dominated by NMDA currents [145,183] – a prediction con ﬁ rmed in vivo [148,184].”
One-dimensional dynamics of attention and decision making in LIP. (2008, background): “There exists a large class of attractor models employing such reverberating feedback either at the level of the single cell (Booth and Rinzel, 1995; Lowenstein and Sompolinsky, 2003) or the local network (Ben-Yishai, et al., 1995; Seung, 1996; Amit and Brunel, 1997; Compte et al., 2000; Wang, 2001).”