Making the Grade with Models of Persistent Activity
Authors: Joshua T. Dudman, Steven A. Siegelbaum
Journal: Neuron (2006)

Persistent neural activity that outlasts an initial stimulus is thought to provide a mechanism for the transient storage of memory. In this issue of Neuron, Fransén et al. identify important principles for a cell-autonomous mechanism of graded persistent firing using an elegant combination of experimental and computational approaches. Persistent neural activity that outlasts an initial stimulus is thought to provide a mechanism for the transient storage of memory. In this issue of Neuron, Fransén et al. identify important principles for a cell-autonomous mechanism of graded persistent firing using an elegant combination of experimental and computational approaches. Many organisms show an impressive capacity to store information for online recall in the performance of memory tasks (Goldman-Rakic, 1990Goldman-Rakic P.S. Prog. Brain Res. 1990; 85: 325-335Crossref PubMed Scopus (357) Google Scholar). This rapid and temporary storage of information during an experimental trial has been called “working memory.” In many behavioral paradigms, individual cells in the prefrontal and medial temporal lobe cortices show persistent firing in the absence of continued sensory input. This persistent activity is thought to form the neural basis for working memory behaviors (Goldman-Rakic, 1995Goldman-Rakic P.S. Neuron. 1995; 14: 477-485Abstract Full Text PDF PubMed Scopus (1860) Google Scholar). How do neurons maintain firing in the absence of sensory input? Two broad classes of solutions have been proposed: reverberatory network activity and intrinsic cell-autonomous persisting firing (Constantinidis and Wang, 2004Constantinidis C. Wang X.J. Neuroscientist. 2004; 10: 553-565Crossref PubMed Scopus (155) Google Scholar). Theoretical and experimental studies have established balanced network activity as a potential mechanism for the maintained firing that is essential for neural functions as diverse as parametric working memory in the primate (Machens et al., 2005Machens C.K. Romo R. Brody C.D. Science. 2005; 307: 1121-1124Crossref PubMed Scopus (362) Google Scholar) and stable eye fixation in the goldfish (Seung et al., 2000Seung H.S. Lee D.D. Reis B.Y. Tank D.W. Neuron. 2000; 26: 259-271Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar). Cell-autonomous maintained firing was, for some time, thought to be more limited—a bistable phenomenon in which neurons can enter a quiescent “down” state or a repetitive firing “up” state (Durstewitz et al., 2000Durstewitz D. Seamans J.K. Sejnowski T.J. Nat. Neurosci. Suppl. 2000; 3: 1184-1191Crossref PubMed Scopus (530) Google Scholar). However, this simple up-down transition does not seem to capture the details of experimental observations. A previous paper from the laboratory of Angel Alonso demonstrated that neurons in layer V of the rat entorhinal cortex can respond to a brief depolarizing stimulus with a maintained period of persistent firing that far outlasts the stimulus (Egorov et al., 2002Egorov A.V. Hamam B.N. Fransen E. Hasselmo M.E. Alonso A.A. Nature. 2002; 420: 173-178Crossref PubMed Scopus (588) Google Scholar). Importantly, this persistent activity was not bistable, but rather the firing frequency of the neuron was a finely graded function of stimulus history. Once initiated, persistent firing could also be terminated in a graded manner in response to a hyperpolarizing stimulus. Traditional computational models of bistable neurons do not capture the richness of this phenomenon. Indeed it has been difficult to understand theoretically how such robust, finely graded activity is generated (Brody et al., 2003Brody C.D. Romo R. Kepecs A. Curr. Opin. Neurobiol. 2003; 13: 204-211Crossref PubMed Scopus (194) Google Scholar). In this issue of Neuron, Fransén and colleagues (Fransén et al., 2006Fransén E. Tahvildari B. Egorov A.V. Hasselmo M.E. Alonso A.A. Neuron. 2006; 49 (this issue): 735-746Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar) return to address the mechanism of graded persistent activity by combining theoretical modeling and experimental approaches. As suggested above, this is not the first attempt to create a model of persistent firing in a neuron; however, it provides important general insights into how such behavior may be generated. Experimental data have demonstrated convincingly that graded persistent activity in the entorhinal cortex requires calcium influx. Indeed, it is thought that persistent firing is generated when a depolarizing stimulus first opens voltage-gated calcium currents. This leads to the rapid activation of both a Ca2+-activated nonselective cation (CAN) current and a calcium-activated K+ current (KCa). Whether or not Ca2+ influx triggers a maintained depolarization that drives persistent firing or leads to repolarization depends on the balance between activation of the depolarizing CAN current and the hyperpolarizing KCa current. Two previous groups have presented models for how CAN current could lead to graded persistent firing (Durstewitz, 2003Durstewitz D. J. Neurosci. 2003; 23: 5342-5353PubMed Google Scholar, Loewenstein and Sompolinsky, 2003Loewenstein Y. Sompolinsky H. Nat. Neurosci. 2003; 6: 961-967Crossref PubMed Scopus (111) Google Scholar). One model involves a positive-feedback loop involving the calcium-activated cationic current and the release of calcium from intracellular stores (Loewenstein and Sompolinsky, 2003Loewenstein Y. Sompolinsky H. Nat. Neurosci. 2003; 6: 961-967Crossref PubMed Scopus (111) Google Scholar). While this model may be relevant to other cell types, Fransén et al. demonstrate experimentally that the depletion of intracellular calcium stores does not prevent the induction of persistent firing in layer V neurons. The other model (Durstewitz, 2003Durstewitz D. J. Neurosci. 2003; 23: 5342-5353PubMed Google Scholar) postulates a delicate balance between the conductance states of a neuron's complement of ion channels. However, persistent firing is shown here to be insensitive to blockade of certain types of channels that are expected to alter excitability. Thus, the question remains as to what mechanisms can meet the rather challenging constraints of the phenomenology of the experimental data, namely robustness, gradation, and persistence. The authors now develop an elegant solution to this problem. Persistent firing is proposed to represent an attractor (i.e., stable physiological state) with a moveable fixed point for the attractor basin. In principle, such a model provides an infinite number of attractor states (that is, different firing frequencies) that are as stable as the process that determines the fixed point (Brody et al., 2003Brody C.D. Romo R. Kepecs A. Curr. Opin. Neurobiol. 2003; 13: 204-211Crossref PubMed Scopus (194) Google Scholar)—features that mimic the essential features of the experimental data. The important insight of the authors is that such behavior can be produced when the basic membrane conductance mechanisms that produce persistent firing are themselves subject to modulation by two opposing Ca2+-dependent processes with separable Ca2+ concentration thresholds. As discussed above, persistent firing is driven by the balance of the CAN current and the KCa current. Initially, at rest, the KCa current exceeds the CAN current elicited by a brief depolarizing stimulus (Figure 1, left). Thus, there is no persistent activity. However, if the stimulus is strong enough, it leads to a larger Ca2+ influx that surpasses a threshold, transiently turning on a biochemical process, such as phosphorylation, that produces a stable increase in the maximal conductance of a subset of CAN channels (Figure 1, middle). This allows the CAN current to exceed the KCa current, resulting in persistent firing that outlasts the brief stimulus. Importantly, the internal Ca2+ level reached during persistent firing is below the threshold required to activate the biochemical cascade needed to alter the CAN conductance. This prevents the development of an explosive feedback loop that would otherwise cause the cell to accelerate its firing rate continuously. However, if a cell receives a subsequent strong stimulus that is capable of elevating Ca2+ past threshold, the biochemical cascade will be triggered once again, leading to a further elevation of firing (Figure 1, right). How does a hyperpolarization diminish the persistent firing frequency or terminate firing altogether? Fransén et al. postulate a second antagonistic biochemical process, akin to dephosphorylation, that becomes activated only when internal Ca2+ levels drop below a minimal threshold value. During repetitive firing, internal Ca2+ remains above this threshold, maintaining the stable firing rate. However, in response to a strong hyperpolarization, Ca2+ will transiently drop below this minimal threshold, triggering a cascade that causes a reduction in the maximal CAN conductance. Once the hyperpolarizing signal terminates, the cell will either resume firing at a decreased frequency or stop firing altogether, depending on the extent of dephosphorylation. Thus, the model of Fransén et al. provides a simple solution to how persistent firing can be both robust yet graded. Robust firing occurs because the thresholds for modification of the fixed point lie outside the normal operating range of intracellular calcium during persistent firing. The modification of the CAN current required to produce continuously graded firing is implemented by the theoretically plausible, although biologically unspecified, signaling pathway that directly modifies the CAN current; a process that is formally analogous to phosphorylation and dephosphorylation. While Fransén and colleagues have identified a robust mechanism for graded persistent firing involving the novel combination of a threshold-dependent biochemical signal and a positive-feedback mechanism through Ca2+ entry and Ca2+-activated cationic channels, a great deal of work remains to be done to map these theoretical features onto their biological implementation. The putative signaling molecules or even the class of second-messenger signaling process is, for the moment, unclear. The details of the cellular basis of working memory have been of great interest, in part, because of the implication of working memory deficits in disease states with genetic linkages (Constantinidis and Wang, 2004Constantinidis C. Wang X.J. Neuroscientist. 2004; 10: 553-565Crossref PubMed Scopus (155) Google Scholar). Such linkages suggest that there may exist molecular mechanisms that are essential and specific for working memory function (Goldman-Rakic, 1995Goldman-Rakic P.S. Neuron. 1995; 14: 477-485Abstract Full Text PDF PubMed Scopus (1860) Google Scholar). In this important study, Fransén et al. establish the principle that a privileged and selective biochemical pathway may explain the cellular processes that underlie some forms of working memory. In so doing, this work provides an important step toward the identification of the molecular basis of working memory behaviors. The identification of a new biochemical pathway may indeed be essential for the remediation of disease states with which deficits in working memory are associated. Mechanism of Graded Persistent Cellular Activity of Entorhinal Cortex Layer V NeuronsFransén et al.NeuronMarch 02, 2006In BriefWorking memory is an emergent property of neuronal networks, but its cellular basis remains elusive. Recent data show that principal neurons of the entorhinal cortex display persistent firing at graded firing rates that can be shifted up or down in response to brief excitatory or inhibitory stimuli. Here, we present a model of a potential mechanism for graded firing. Our multicompartmental model provides stable plateau firing generated by a nonspecific calcium-sensitive cationic (CAN) current. Sustained firing is insensitive to small variations in Ca2+ concentration in a neutral zone. Full-Text PDF Open Archive