David Naylor, MD, PhD
Investigator, The Lundquist Institute
Research DescriptionDr. Naylor’s laboratory utilizes a multidisciplinary approach that includes experimental techniques mainly of in vitro visualized whole-cell patch-clamp electrophysiology and pharmacology in brain slices in conjunction with multi-scale computational modeling primarily of inhibitory GABAergic and excitatory glutamatergic receptors at synaptic and extrasynaptic sites. Stereotactic in vivo electrophysiology also is a component of the lab research.
This combination of disciplines reveals with high spatio-temporal precision how subtle micro-level changes in receptor properties with disease or therapeutic intervention affect macro-level neural circuit behavior. When activated, individual receptors enter into various bound, open, closed, and desensitized states that each correlate with particular conformational shifts of structure. A bias towards particular state-conformations depends on receptor subunit-subtype composition, binding of transmitter and pharmacological agents, as well as factors such as temperature and pH.
The computational model parameters for receptor numbers, state transitions, and the spatio-temporal profile of transmitter in and outside the synapse are optimized to precisely fit the experimentally measured physiology of inhibitory and excitatory postsynaptic currents, tonic extrasynaptic currents, and stimulus-evoked currents. Very hi-resolution dynamic detail is provided on sub-millisecond temporal and synaptic (10s - 100s nanometer) spatial dimensions simultaneously and in situ.
Advantages of this multidisciplinary include the ability to causally and simultaneously relate how multiple micro-level disturbances determine macro-level circuit pathophysiology. In addition, the computational receptor models are useful tools for sensitive screening of micro- macro-level drug actions, optimization of drug combinations, and off-line simulations of drug actions under control and difficult to record pathological conditions.
Dr. Naylor’s research currently is focused on the following areas:
1) Disease effects on circuit plasticity:
Because of the structural-functional relation between protein conformation and receptor kinetic states, the lab is exploring how a disease process or drug exposure can bias particular receptor states/conformations thereby exposing sites for phosphorylation or phosphatase action and increasing susceptibility to receptor trafficking and long-term plasticity changes.
2) Pharmacology models:
Drugs bind and have direct actions on receptor kinetic states, but also impact broader circuit function for therapeutic effect. Many drugs increase activation by increasing ligand-binding affinity and entry into ion-conducting ‘open’ states, but have paradoxical and untoward effects of also increasing entry into nearby desensitized states. By applying various classes of drugs while recording excitatory and/or inhibitory postsynaptic & tonic currents, a quantitative representation for an agent’s action on a particular receptor and on circuit activity is provided that detects subtle differences between drugs, even within class, that may include less risk for desensitization and receptor trafficking associated with tolerance & addiction after chronic drug exposure.
3) Hypothermia mechanisms:
Hypothermia - a standard therapy for brain injury after post-anoxic cardiac arrest and other CNS insults - often is associated with status epilepticus during re-warming. The lab has found receptor and synaptic changes with temperature indicating increases in GABAergic inhibition at lower temperatures thereby explaining a loss of inhibition and lowering of seizure threshold with re-warming or with elevated temperatures during febrile seizures. Temperature exhibits a differential effect on drug actions with an occlusion of phenobarbital - but relative sparing of benzodiazepine - action at low temperatures that can be attributed to an overlap of drug and temperature effects on receptor kinetics with phenobarbital.
Recent and/or Significant Publications
Niquet J, Baldwin R, Suchomelova L, Lumley L, Naylor D, Eavey R and Wasterlain CG. Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment. Ann NY Acad Sci. 2016; 1378:166-173.
Naylor DE. Prolonged Epileptic Seizures: identification and treatment. Treating acute seizures with benzodiazepines: does seizure duration matter? Epileptic Disorders. 2014; 16 Suppl 1:69-83.
Naylor DE, Liu H, Niquet J and Wasterlain CG. Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus. Neurobiology of Disease. 2013; 54:225-38.
Wasterlain CG, Naylor DE, Liu H, Niquet J, Baldwin R. Trafficking of NMDA receptors during status epilepticus. Epilepsia. 2013; 54 Suppl 6:78-80.
Naylor DE. Glutamate and GABA in the balance: convergent pathways sustain seizures during status epilepticus. Epilepsia. 2010; 51 Suppl 3:106-109.