The proposed experiments of this Merit Review competitive renewal are part of the effort by many labs to determine how central nervous system neurons encode their synaptic inputs. In particular, the experiments are designed to determine how specific neurons (or abnormal function of those neurons) contribute to synchronous network activity that occurs both during normal signal processing and during seizure activity. The major questions are 'What temporal aspects of natural patterns of synaptic activity are most effective for driving a neuron's action potential firing?'and 'What are the underlying mechanisms?'We focus on the responses of principal cells in neocortex (pyramidal neurons) to local circuit activity. The convergent synaptic activity generated by cortical networks has a broad frequency spectrum, similar to random noise. We have shown that the pyramidal neurons show resonant firing to this type of input. That is, specific frequency components of their input drive firing better than others. Two input frequencies cause the resonance: theta (~7 Hz) and fast ripple (~300 Hz). Additional studies point to certain potassium conductance mechanisms as being critical for the type and amount of resonance a pyramidal neuron has. A mutation in the gene (KCN1) for one of these potassium channels (Kv1) and antibodies against the Kv1.1 protein are known to cause spontaneous and excessive discharges of central neurons in humans, leading to problems with motor function. Our current proposal includes three sets of experiments. In the first we will determine the role of Kv1 channels in dendritic filtering of excitatory inputs. In the second set we will determine the effect of Kv1 channels on the suprathreshold responses to dendritic inputs (e.g. resonant firing). In the third set we will examine the changes in neuronal excitability caused by normal and pathologic up-regulation of dendritic Kv1.1 channel subunits. The methods employ patch pipettes to record from visualized neurons in brain slices. Neurons are stimulated by 2-photon photolysis of caged glutamate near spines on dendrites. Neurons are also stimulated in current clamp and dynamic clamp using computer-generated waveforms that simulate the statistics of ongoing synaptic activity arriving at the soma (focusing mostly on excitatory inputs). To investigate how potassium channels affect the responses, potassium channel blockers are applied to the neurons during the electrical recording. Anatomical classification of neurons is done by intracellular staining with a fluorescent dye.

Public Health Relevance

Traumatic brain injury is a major cause of epilepsy in our veteran patient population. Epilepsy caused by injury to the neocortex is hard to manage medically, and the surgical options are more restricted than for temporal lobe epilepsy. So we need to find better ways to treat this problem. Particular frequency components of neocortical network activity are specifically associated with seizures and promote their initiation and propagation. Other frequencies may be suppressive. We expect that the proposed studies will close major gaps in our basic understanding of both normal and pathological neocortical oscillations and provide a rational basis for the design of new treatments for epilepsy.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology C (NURC)
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VA Puget Sound Healthcare System
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Tao, Wucheng; Higgs, Matthew H; Spain, William J et al. (2013) Postsynaptic GABAB receptors enhance extrasynaptic GABAA receptor function in dentate gyrus granule cells. J Neurosci 33:3738-43
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