UC San Diego

The regulation of transmembrane ionic and synaptic currents is crucial for maintaining physiological neural activity and allow brain networks to be resilient to external perturbations. To this effect, the brain implements many homeostatic mechanisms by which it can control neuronal excitability and communication by maintaining ionic concentration gradients and synaptic strengths within a physiological range. Indeed, there exist many membrane-bound transporter proteins which function to move ions across the plasma membrane to re-establish resting ionic gradients following changes in neuronal spiking. Similarly, the nervous system has developed homeostatic mechanisms by which it can regulate the strength of synaptic connections by augmenting the number of excitatory post-synaptic receptors present in an activity-dependent manner. It is traditionally thought that a breakdown of these mechanisms may underlie various neurological and psychiatric disorders. Though much has been learned about ionic and synaptic regulation of single neuron activity, how these homeostatic mechanisms give rise to or influence physiological and pathological brain states remains to be fully understood. Here we explore the roles of ionic and synaptic homeostasis in the regulation of network dynamics. We begin by first demonstrating that in the pathological brain (i.e. one riddled with K-channelopathies or suffering traumatic brain injury) these network stabilizing mechanisms can overcompensate for the chronic network perturbations resulting in hyperexcitability and lowered thresholds for seizure generation. We then demonstrate that the regulation of ionic concentration gradients in the healthy brain can give rise to infra-slow network fluctuations, which may underlie various brain-state transitions and cognitive states. Together these studies highlight the importance of proper ionic and synaptic regulation for the maintenance of physiological activity and transitions to pathological states and provides new insight into the development of interventions that can be used to treat epileptic seizures.