The sodium-potassium pump is an information processing element in brain computation

Brain neurons can transmit signals using a flow of Na+ and K+ ions, which produce an electrical spike called an action potential (AP) (Hodgkin and Huxley, 1952). After an AP, the Na+/K+ pump resets the arrangement of Na+ and K+ ions back to their original positions so that the neuron is then ready to relay another AP when it is called upon to do so (Glitsch, 2001). So, the Na+/K+ pump has a “housekeeping” role rather than a direct role in brain signaling. This is the long-held, entrenched viewpoint. However, novel research upon cerebellar Purkinje neurons suggests that the Na+/K+ pump may have a direct role in brain coding and computation (Forrest, 2008, 2014a,b; Forrest et al., 2009, 2012). This research was conducted in 2006–2007, and presented in a 2008 Ph.D. thesis (Forrest, 2008), but has only been published relatively recently. In the intervening period it was serially rejected by reviewers and journals that were uncomfortable with this re-appraisal of Na+/K+ pump function. Purkinje neurons are found in the cerebellum, responsible for motor control (Ito, 1984). The Na+/K+ pump uses the energy of one ATP molecule to exchange three intracellular Na+ ions for two extracellular K+ ions (Glitsch, 2001). Thus, the pump is electrogenic, extruding one net charge per cycle to hyperpolarize the membrane potential. In vitro, the Na+/K+ pump has been shown to control and set the intrinsic activity mode of Purkinje neurons (Forrest, 2008, 2014a; Forrest et al., 2009, 2012). It dictates whether the Purkinje neuron is quiescent or spontaneously firing in a continuous tonic, continuous burst, bimodal (tonic and quiescent), trimodal (tonic, burst, quiescent), or bimodal (burst and quiescent) repeat pattern. In the bimodal and trimodal repeat patterns, the Na+/K+ pump sets the length of each constituent mode. So, at the foundation of the Purkinje cell’s intrinsic multimodality, there is the working of just a single molecular species: the Na+/K+ pump. Numerical modeling of experimental data suggests that, in vivo, the Na+/K+ pump produces long quiescent punctuations (>>1 s) to Purkinje neuron firing (Forrest, 2014a). The Na+/K+ pump is an enzyme and its activity is dependent on the concentration of its substrates: intracellular Na+ and extracellular K+ (Glitsch, 2001). Na+ flows into and accumulates in the Purkinje cell during firing; Forrest’s numerical model proposes that intracellular Na+ concentration is a memory element, which records firing history (Forrest, 2014a). Furthermore, that the Na+/K+ pump “reads” this memory setting to dictate the timing and duration of long quiescent periods. To speculate, these long quiescent periods, on the scale of seconds and minutes, may be computationally advantageous. By conferring an access to longer time scales, they may permit storage and short-term processing of sensory information in the cerebellar cortex. To elaborate, they may permit different dynamical states to be sustained in the cerebellar cortex for extended periods. Each of these states is associated with a specific configuration of firing and quiescent states in different Purkinje cells. These network states could store information and perform computations. So, these network computations sit upon the proposed intracellular Na+ ion computation, mediated by the Na+/K+ pump, which dictates the activity state of individual Purkinje neurons (firing or quiescent). Forrest terms this hypothesis: “ion to network” computation (Forrest, 2014a). There could be further layers of control and regulation: the Na+/K+ pump is a receptor for the endo-ouabain signaling molecule (Xie and Cai, 2003) and Na+/K+ pump activity might be modulated by intracellular signaling cascades (Therien and Blostein, 2000; Bagrov and Shapiro, 2008). Relevantly, a mutation in the Na+/K+ pump causes rapid onset dystonia parkinsonism, which has symptoms to indicate that it is a pathology of cerebellar computation (Cannon, 2004; de Carvalho et al., 2004). Furthermore, an ouabain block of Na+/K+ pumps in the cerebellum of a live mouse results in it displaying movement disorders: ataxia and dystonia (Calderon et al., 2011). In recent times, other groups have shown the Na+/K+ pump to be a computational element in other neuron types, in other systems. For example, the Na+/K+ pump produces an afterhyperpolarization (AHP) to each burst in the motor neurons of Drosophilia larvae; AHP amplitude is dependent on the number of spikes in the burst (Glanzman, 2010; Pulver and Griffith, 2010). So the Na+/K+ pump generated AHP acts as a spike counter and is a form of short-term memory. Locomotion in Xenopus tadpoles, as in vertebrates generally, is produced by a central pattern generator (CPG) network