Investigating the impact of 14-3-3 protein knockout on excitability of hippocampal CA1 pyramidal neurons

14-3-3 proteins are a family of regulatory proteins that are enriched at synaptic junctions. Many neurological and psychiatric disorders have also been linked to 14-3-3 protein dysfunctions. Our lab has previously shown that 14-3-3 protein functional knockout mice have reduced expression of synaptic proteins (including NMDA receptor subunits), deficits in hippocampal long-term potentiation, and desynchronization in theta waves between hippocampus and prefrontal cortex. In addition, the 14-3-3 functional knockout mice exhibit behavior that correspond with the symptoms of psychiatric disorders such as schizophrenia. Recently, using cFos staining as an indicator, we identified an increase in activity in hippocampal CA1 and dentate gyrus neurons expressing the 14-3-3 inhibitor. However, it is not clear whether this increased neuronal activity is caused by altered synaptic activity, enhanced single cell excitability, or both. In this work, we are using slice electrophysiology and whole cell patch clamp to evaluate the impact of 14-3-3 inhibition on electrophysiological properties of hippocampal CA1 pyramidal neurons. To assess 14-3-3 knockout induced excitability changes, we measure differences in rheobase and firing rate between the 14-3-3 knockout mouse and their wild type control using current clamp. We are also using voltage clamp to identify changes in inward and/or outward current in these neurons. Additionally, we measure both miniature and spontaneous inhibitory and excitatory synaptic currents to assess potential alterations in synaptic input to the neurons in the 14-3-3 functional knockout mouse. We expect this study to provide critical insight that links the dysfunction of these regulatory proteins to the altered neuronal and/or synaptic activity, which may underline the neural circuitry and behavioral aberrations exhibited in these functional knockout mice. © FASEB.