Joseph Glykys, MD, PhD
Assistant Professor of Neurology, Harvard Medical School
Assistant in Neurology, Massachusetts General Hospital
Building 114, Charlestown Navy Yard
114 16th Street, Room 2502
Charlestown, MA 02129
Explore This Lab
Dr. Glykys is a child neurologist and his main research interests are:
- How the brain inhibition system works at the cellular level
- How the dysfunction in the inhibition system can lead to seizures with special emphasis in post-traumatic seizures and neonatal seizures
One of our main problems with pediatric seizures is the significant failure rate of our current medical treatments due to an incomplete understanding of how the inhibitory system works in the brain.
The neurotransmitter GABA mediates inhibition in the mature brain. However, GABA can actually excite a neuron during early development and after brain insults. The net action of GABA depends on the relation between the chloride (Cl-) concentration inside and outside the neuron. In mature neurons, Cl- is low inside the neurons. In early development and pathological conditions, Cl- is high in neurons. When GABA binds to its receptor, it opens a channel that allows the flow of Cl- until it reaches a point where no more can move (its equilibrium potential [ECl]). Thus, if a neuron has lowCl-, GABA will allow Cl- to enter the neuron and inhibit it. When Cl- is high, GABA will allow Cl- to exit the neuron and depolarize it.
One therapeutic approach to enhance inhibition in the brain is to decrease the neuronal Cl-concentration and improve the efficacy of anticonvulsive medications that activate GABAA receptors. We use electrophysiology and 2-photon imaging of a Cl- sensitive genetically encoded fluorophore to address our scientific questions.
Our results will not only provide new treatments for pediatric seizures but will also be applicable to other brain injuries that lead to Cl- increase like traumatic brain injury. We will also better understand how the brain’s inhibitory network works.
Pediatric Traumatic Brain Injury and Cl- dysregulation
Severe head trauma causes widespread neuronal shear injuries and acute seizures. Shearing of neural processes might contribute to seizures by disrupting the trans-membrane ion gradients, including the intracellular Cl- concentration [Cl-]i. By using 2-photon imaging of Clomeleon (a Cl- sensitive genetically encoded fluorophore) we have demonstrated that acute brain trauma causes an increase in [Cl-]i in the most superficial neurons in the neocortex, thalamus and hippocampus in vitro and at different developmental ages. Yet, the deeper uninjured neurons show the natural progressive developmental decrease in [Cl-]i. These data support that acute brain trauma causes an elevation in neuronal [Cl-]i and can lead to excitatory actions of GABA.
Current projects involve studying how [Cl-]i modulation can decrease neocortical seizure activity using an in vitro model of pediatric traumatic brain injury.
The neuronal [Cl-]i determines if a neuron is inhibited or excited when GABA binds to the GABAAreceptor. Our most recent results support the idea that cytoplasmic impermeant anions and polyanionic extracellular matrix glycoproteins set the local [Cl-]i while cation-chloride cotransporters (CCCs) move Cl-and water across the membrane in favor of this set point. Our new hypothesis suggests that modulating CCCs can alter GABA mediated transmission and neuronal volume , and altering the extracellular matrix can also be an effective way to treat increased [Cl-]i due to brain injury.
Current projects involve studying the relation between neuronal Cl- and volume regulation and how they are altered during traumatic brain injury.
Read about and apply for residency, fellowship and observership programs at the neurology education page.
Glykys, J., Staley KJ. (2016). Developmental Decrease of Neuronal Chloride Concentration Is Independent of Trauma in Thalamocortical Brain Slices. PLoS One. Jun 23;11(6):e0158012. doi: 10.1371/journal.pone.0158012. eCollection 2016.
Glykys, J., Staley, J. (2015). Diazepam effect during early neonatal development correlates with neuronal Cl−. Ann Clin Transl Neurol. Oct 27;2(12):1055-70. doi: 10.1002/acn3.259. eCollection 2015 Dec.
Benowitz I, Cohen AR, Glykys J., Gorstein SV, Burns MM, Miller ES. (2015) An Altered, Unresponsive Teenager in the Emergency Department. J Emerg Med. Jan;50(1):116-20. doi: 10.1016/j.jemermed.2015.09.023. Epub 2015 Oct 21.
Glykys J., Dzhala V, Egawa K, Balena T, Saponjian Y, Kuchibhotla KV, Bacskai BJ, Kahle KT, Zeuthen T, Staley KJ.(2014). Response to comments on "Local impermeant anions establish the neuronal chloride concentration". Science. 345(6201):1130.