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 injury. 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. In our initial studies, we examined the recruitment of fast GABAergic inhibitory events in rodent neocortex. These studies showed that fast GABAA-mediated inhibition is strictly limited relative to synaptic excitation, and that neocortical inhibitory circuits are driven predominantly by non-NMDA (AMPA/kainate) excitatory transmission. Our more recent studies have indicated 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 counter states of hyperexcitation.
Using a rodent-based model of TBI, we are also investigating trauma-induced changes in cortical physiology. These studies have indicated that injury to the superficial neocortex (which includes layers I, II, and part of III) can lead to epileptogenesis, manifested as hyperexcitability and evoked epileptiform activity. 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 this model, post-injury administration of neuroprotective agents, such as antiepileptic drugs, can prevent the development of trauma-induced epileptogenesis. Our recent studies indicate that certain nootropic agents may also be neuroprotective in this model. 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 injury.
Our laboratory uses a variety of techniques that include electrophysiology, histology, microscopy, and animal 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 neuropathophysiologies caused by TBI.
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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 in vitro. 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 M is necessary and sufficient for LTP maintenance. Nat. 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. 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 somatosensory cortex. Neuroscience Lett. 416, 221-226.
Lie Yang, M.D., Ph.D., Research Assistant Professor
Sonia Afroz, Brooklyn College Undergraduate Student
Special Scientific Review Board, CURE (Citizens United for Research in Epilepsy), Special Program for the Prevention of Epilepsy After Traumatic Brain Injury.
Ad hoc reviewer, Department of Defense Grant Program for Posttraumatic Stress Disorder and Traumatic Brain Injury.
Reviewer for various journals.