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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039579-12
Application #
8239973
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
1999-12-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$344,543
Indirect Cost
$130,168
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
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
Li, Huifang; McDonald, Whitney; Parada, Isabel et al. (2011) Targets for preventing epilepsy following cortical injury. Neurosci Lett 497:172-6
Jin, Xiaoming; Huguenard, John R; Prince, David A (2011) Reorganization of inhibitory synaptic circuits in rodent chronically injured epileptogenic neocortex. Cereb Cortex 21:1094-104
Manseau, Frederic; Marinelli, Silvia; Mendez, Pablo et al. (2010) Desynchronization of neocortical networks by asynchronous release of GABA at autaptic and synaptic contacts from fast-spiking interneurons. PLoS Biol 8:
Faria, Leonardo C; Prince, David A (2010) Presynaptic inhibitory terminals are functionally abnormal in a rat model of posttraumatic epilepsy. J Neurophysiol 104:280-90
Brill, Julia; Huguenard, John R (2009) Robust short-latency perisomatic inhibition onto neocortical pyramidal cells detected by laser-scanning photostimulation. J Neurosci 29:7413-23
Prince, David A; Parada, Isabel; Scalise, Karina et al. (2009) Epilepsy following cortical injury: cellular and molecular mechanisms as targets for potential prophylaxis. Epilepsia 50 Suppl 2:30-40
Beenhakker, Mark P; Huguenard, John R (2009) Neurons that fire together also conspire together: is normal sleep circuitry hijacked to generate epilepsy? Neuron 62:612-32

Showing the most recent 10 out of 18 publications