Cellular Sources Of Neuregulin 1 (NRG1) Regulating Neural Activity And Behavior

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Project Summary Schizophrenia (Sz) affects 1% of the population worldwide and places a costly and painful burden on patients, their families and society. Currently there are no treatments available to effectively rehabilitate Sz patients. The neurotrophic factor Neuregulin 1 (NRG1) is a promising therapeutic target because the gene is associated with Sz in various populations, and NRG1 levels are altered in Sz. NRG1 stimulates the ErbB family of tyrosine kinase receptors, including ErbB4, which is associated with Sz. NRG1 signaling via ErbB4 receptors expressed in parvalbumin (PV)-positive interneurons promotes neural processes important for executive functions which are impaired in Sz. A critical barrier to progress in improving treatment of Sz is a lack of understanding of whether the cells, which produce the NRG1 resulting in release of GABA or stimulation of gamma oscillations, also supply the NRG1 involved in suppression of LTP or seizure activity. Our goal is to improve the treatment of Sz by obtaining the information and understanding needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Our central hypothesis is that different cellular sources of NRG1 differentially and selectively impact synaptic transmission, network activity and behavior, and that these unique cellular functions are potential mechanisms by which NRG1 could suppress seizures as well as promote network activity important for higher brain functions. Our objectives are to 1) determine the cell-type specific roles of neuronal and astrocytic NRG1 in GABA transmission, gamma oscillations, LTP, epileptogenesis, and Sz-relevant mouse behaviors and 2) provide clarification of the cellular sources of NRG1 involved in mechanisms regulating excitatory-inhibitory balance within local circuits, and facilitating transfer of information from hippocampus to cortex. Our expected outcomes include 1) knowledge of the cellular origins of NRG1 engaged during different states of synaptic and network activity, 2) improved understanding of the neuronal and astrocytic mechanisms underpinning NRG1 activation of ErbB4, and 3) new insights into the specific roles played by astrocytic and neuronal NRG1 in behaviors requiring cognitive functions often impaired in Sz. The impact of our findings will provide a stronger rationale for therapeutically targeting NRG1 during pathological conditions, as well as an improved knowledge base, which is needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Aim 1 will test the hypothesis that NRG1 derived from principal neurons, interneurons and astrocytes differentially regulates excitatory and inhibitory synaptic transmission. Aim 2 will test the hypothesis that NRG1 derived from these three different cell types differentially regulate Sz-relevant behaviors.