Presynaptic mechanisms controlling excitatory and inhibitory synaptic transmission in the cerebral cortex have critical roles in normal information processing and also may contribute to the pathophysiology of a variety of brain disorders such as cognitive decline and epilepsy.
The specific aims of these experiments focus primarily on inhibitory synaptic transmission mediated by gamma-amino butyric acid (GABA)-containing inhibitory interneurons and its regulation by 3 potent and ubiquitous processes in normal cerebral cortex and in a model of posttraumatic epileptogenesis. These neurons are known to be vulnerable to injury.
Specific aims relate to (1) control of transmitter release by presynaptic Ca++ channels and (2,3) modulatory effects on GABAergic inhibition produced by actions of neuropeptide Y and GABA at their receptors and selective Ca++ current blockers on presynaptic terminals of major classes of inhibitory interneurons. Techniques employed include use of whole cell patch clamp recordings of spontaneous and evoked inhibitory postsynaptic currents (IPSCs) generated by identified subclasses of interneurons in in vitro brain slices;laser scanning photostimulation to map cortical connectivity;paired recordings to examine unitary IPSCs from interneurons to other interneurons and pyramidal cells;use of genetically engineered mice with GFP label in specific interneuron species;and local application or bath perfusion of receptor agonists and antagonists. The partial cortical isolation model will be used to provide chronically injured, epileptogenic neocortical slices and assess changes in these presynaptic modulatory mechanisms that might contribute to hyperexcitability. The long term goals are to identify critical abnormalities that might eventually be targets for selective agents that would used to prevent or treat human posttraumatic epilepsy.
Epilepsy following brain injury is a major health problem. The mechanisms that lead from injury to epilepsy in man are poorly understood however loss of the ability to inhibit or """"""""quiet"""""""" nerve cells with the chemical messenger, GABA, is one key underlying factor. The proposed experiments will use a model of posttraumatic epilepsy to better understand how nerve cells regulate GABA release in normal and injured brain, what might go wrong after brain injury, and how that knowledge might be used to improve approaches for prevention and treatment of epilepsy.
|Gu, Feng; Parada, Isabel; Shen, Fran et al. (2017) Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis. Neurobiol Dis 108:100-114|
|Brill, Julia; Mattis, Joanna; Deisseroth, Karl et al. (2016) LSPS/Optogenetics to Improve Synaptic Connectivity Mapping: Unmasking the Role of Basket Cell-Mediated Feedforward Inhibition. eNeuro 3:|
|Takahashi, D Koji; Gu, Feng; Parada, Isabel et al. (2016) Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma. Neurobiol Dis 91:166-81|
|Prince, David A (2014) How do we make models that are useful in understanding partial epilepsies? Adv Exp Med Biol 813:233-41|
|Jin, Xiaoming; Jiang, Kewen; Prince, David A (2014) Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria. J Neurophysiol 112:1703-13|
|Mantoan Ritter, Laura; Golshani, Peyman; Takahashi, Koji et al. (2014) WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55:1693-702|
|Ma, Yunyong; Ramachandran, Anu; Ford, Naomi et al. (2013) Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia 54:1232-9|
|Mao, Rong; Schummers, James; Knoblich, Ulf et al. (2012) Influence of a subtype of inhibitory interneuron on stimulus-specific responses in visual cortex. Cereb Cortex 22:493-508|
|Faria, Leonardo C; Parada, Isabel; Prince, David A (2012) Interneuronal calcium channel abnormalities in posttraumatic epileptogenic neocortex. Neurobiol Dis 45:821-8|
|Ma, Yunyong; Prince, David A (2012) Functional alterations in GABAergic fast-spiking interneurons in chronically injured epileptogenic neocortex. Neurobiol Dis 47:102-13|
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