Abstract : 

Spontaneous firing, observed in many neurons, is often attributed to ion channel or network level noise. In addition to in vivo, it is widely observed in slices of cholinergic interneurons, cerebellar Purkinje cells and even brainstem inspiratory neurons. In such in vitro preparations, where the functional relevance is long lost, neurons continue to display a rich repertoire of firing properties. It is perplexing that these neurons, instead of saving their energy during information downtime and functional irrelevance, fire metabolically costly action potentials. We propose that spontaneous firing is not a chance event but instead, a vital activity for the well-being of a neuron.

According to this hypothesis, neurons, in anticipation of synaptic inputs, keep their ATP levels at maximum, to allow quick recovery from synaptic inputs that perturb the balance of ionic concentrations. It follows that during synaptic quiescence neurons are ATP-rich and ADP-scarce. ADP thus serves as the rate-limiting step of ATP production, stalling out the last step of a long chain of biochemical processes at the Complex V in mitochondria. 

Stalling this ATP production line leads to toxic Reactive Oxygen Species (ROS) formation. ROS disrupts many cellular processes and its prolonged exposure challenges cell survival. We hypothesize that spontaneous firing occurs in these conditions, as a release valve to produce ADP and thus restore ATP production, shielding neurons against ROS. We propose that spontaneous firing as ROS defense is an intrinsic neuronal mechanism that coexists with conventional synaptic input integration and network wide functions utilize both these mechanisms.

By linking a mitochondrial metabolism model to a conductance-based neuron model, we show that - in agreement with our hypothesis -  spontaneous firing in a neuron can be affected by baseline ATP usage and ATP-cost-per-spike. From our model emerges a survival-centric, mitochondrial mediated homeostatic mechanism, that assigns new roles for voltage-gated ion channels and provides a possible explanation for the many different intrinsic firing patterns observed in neuronal recordings. Our findings focus on intracellular dynamics but suggest large knock-on effects on the nature of neural coding. Additionally, our hypothesis offers a new way to reconcile with etiology of neurodegenerative diseases such as Parkinson's disease.


Chaitanya Chintaluri is a postdoctoral researcher in the Vogels Lab at the University of Oxford (soon IST Austria).
Chaitanya has a B.E. in Electronics and Electrical engineering, and M.Sc. in Physics from BITS Pilani, India. He worked as a Junior Research Fellow at NCBS, India in the laboratory of Prof. Upinder Bhalla, where he contributed in the development of a user interface for the neural simulator MOOSE and built a visualization tool called Moogli. Chaitanya obtained his PhD in the laboratory of neuroinformatics, led by Prof. Daniel Wójcik at the Nencki Institute of Experimental Biology, Poland. For his PhD, Chaitanya studied the propagation of electric currents in brain tissue and built a tool for current source density reconstruction called kCSD.

Click here to register via Eventbrite