Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality worldwide, affecting approximately 1.5 million patients per year in the United States alone. Unfortunately, there are presently no clinical treatments that have been proven effective in reducing the long-term neurological disabilities that result from TBI. A better understanding of the changes in neural circuit function caused by TBI is essential to the development of improved therapeutics.
Our lab is investigating the properties of cortical neuronal circuits and the changes in neural activity caused by TBI. Normal activity in the central nervous system is regulated by the critical balance between synaptic excitation and inhibition, the latter primarily mediated by the neurotransmitter GABA. If this balance is disrupted, states of hyperexcitation can develop and lead to neuropathologies such as epilepsy, excitotoxic cell damage, and cognitive disorders. The somatosensory cortex (neocortex) seems to be particularly susceptible to the development of unrestrained excitation. One factor contributing to this vulnerability may be an intrinsic limit on the recruitment of GABA inhibition, such that rising excitation can build to levels that exceed the capacity of inhibitory mechanisms to contain. Clearly, inhibitory interneurons play a key role in maintaining the stability of cortical network activity. Thus, an understanding of inhibitory circuits is crucial to understanding not only normal neuronal population activity, but also states of pathophysiological activity, such as those caused by TBI.
Cortical inhibitory circuits are comprised of interneurons that release GABA onto pyramidal neurons (the principal cells of the neocortex), causing a membrane hyperpolarization that counterbalances excitatory inputs. Our studies have shown that in neocortex, the recruitment of fast GABAergic inhibition is strictly limited relative to synaptic excitation, and that neocortical inhibitory circuits are driven predominantly by non-NMDA (AMPA/kainate) excitatory transmission. We have also found that nootropic (cognition-enhancing) drugs, which are positive modulators of AMPA receptors, enhance the recruitment of GABAergic inhibition through actions on inhibitory interneurons and thus, might serve as a new pharmacological approach to boost inhibitory cell output and, in turn, counteract pathophysiologic states of hyperexcitation.
Using both in vitro and in vivo rodent-based models of TBI, we are investigating trauma-induced changes in cortical physiology that give rise to neuropathologies, such as cognitive dysfunction and posttraumatic epileptogenesis. Thus far, our studies have shown that injury to the superficial layers of the neocortex leads to neuron degeneration and epileptogenesis, manifested as neural circuit hyperexcitability and spontaneous epileptiform activity that includes prolonged, ictal-like discharges. This is caused by a disinhibition of cortical circuits that stems from two sources: (1) a decrease in GABAergic inhibition; and (2) a persistent increase in glutamatergic excitation. In our TBI models, post-injury administration of neuroprotective agents, such as antiepileptic drugs and certain nootropic agents, can prevent the development of posttraumatic epileptogenesis. However, in all cases, drug efficacy appears to be critically dependent on the timing of administration, suggesting a narrow therapeutic time window for effective anti-epileptogenic interventions following cortical neurotrauma.
Our laboratory uses a variety of techniques that include electrophysiology, histology, microscopy, and behavioral testing to explore the pathological effects of TBI on cortical circuit function. Our goals include the development of effective therapeutic interventions to prevent or mitigate the neuropathophysiologies caused by TBI.
Our other research projects include a collaborative effort to develop radiofrequency-based interrogation techniques to non-invasively detect and record neural signals from cortical circuits. Such technology could enable rapid, field-forward diagnosis of trauma-induced pathophysiologies in cortical function, including epileptic activity, and could also facilitate the acquisition of neural signals for improved brain-machine interfaces.
Ling, D. S. F., and Benardo, L. S. (1995). Recruitment of GABAA inhibition in rat neocortex is limited and not NMDA dependent. J. Neurophysiol. 74, 2329-2335.
Ling, D. S. F., and Benardo, L. S. (1998). Synchronous firing of inhibitory interneurons results in saturation of fast GABAA IPSC magnitude but not saturation of fast inhibitory efficacy in rat neocortical pyramidal cells. Synapse 28, 91-102.
Ling, D. S. F., and Benardo, L. S. (1999). Restrictions on inhibitory circuits contribute to limited recruitment of fast inhibition in rat neocortical pyramidal cells. J. Neurophysiol. 82, 1793-1807.
Ling, D. S. F., Benardo, L. S., Serrano, P. A., Blace, N., Kelly, M. T., Crary, J. F., and Sacktor, T. C. (2002). Protein kinase Mζ is necessary and sufficient for LTP maintenance. Nature Neurosci. 5, 295-296.
Ling, D. S. F. and Benardo, L. S. (2005). Nootropic agents enhance the recruitment of fast GABAA inhibition in rat neocortex. Cerebral Cortex 15, 921-928.
Ling, D. S. F., Benardo, L. S., and Sacktor, T. C. (2006). Protein kinase Mζ enhances excitatory synaptic transmission by increasing the number of active postsynaptic AMPA receptors. Hippocampus 16, 443-452.
Yang, L., Benardo, L. S., Valsamis, H., and Ling, D. S. F. (2007). Acute injury to superficial cortex leads to a decrease in synaptic inhibition and increase in excitation in rat neocortex. J. Neurophysiol. 97, 178-187.
Yang, L. and Ling, D. S. F. (2007) Carbenoxolone modifies inhibitory and excitatory spontaneous synaptic transmission in rat somatosensery cortex. Neurosci. Lett. 416, 221-226.
Yang, L., Afroz, S., Michelson, H. B., Goodman, J. H., Valsamis, H. A., and Ling, D. S. F. (2010). Spontaneous epileptiform activity in rat neocortex after controlled cortical impact injury. Journal of Neurotrauma 27, 1541-1548.
Sebastian, V., Diallo, A., Ling, D. S. F., and Serrano, P. A. (2013). Robust training attenuates TBI-induced deficits in reference and working memory on the radial 8-arm maze. Front. Behav. Neurosci. 7:38.
Lie Yang, M.D., Ph.D., Research Assistant Professor
Ad hoc reviewer, Department of Defense Grant Program for Posttraumatic Stress Disorder and Traumatic Brain Injury.
Reviewer for various journals.