Homeostatic regulation of inhibition is a fundamental problem faced by many neural circuits. However, the rules governing homeostasis of inhibitoty neurons may differ from those operating in excitatory neurons, since the inhibitory neurons must he regulated, not only by their own firing, but by the overall level of actirity in the circuit. Altered homeostatic regulation of inhibition has been implicated in brain disorders including schizophrenia, autism and autism spectrum disorders and epilepsy. Furthermore, genes implicated in these disorders have potent actions on specific subtypes of cortical interneurons, but the relationships between these pathways and homeostatic regulation of actirity are incompletely understood. We vrill investigate the role of DNA methylation in regulating the "setpoint" or "operating range" of the largest subgroup of cortical interneurons, the parvalbumin positive fast-spiking (FS) neurons in mice. We vrill study the physiological, epigenetic, and transcriptional consequences of deleting enzymes that mediate methylation, selectively in these neurons . We vrill study the interaction between this regulation and regulation by actirity and other signaling pathways known to regulate these neurons including neuregulin 1 and its receptor ErbB4. In a second set of studies we investigate the role of micro RNA pathways in homeostatic plasticity of FS cell excitabUity, first by deleting the bios3nithetic enzyme dicer in FS neurons, and then by using novel profiling methods to identify actirity regulated microRNAs in these neurons. Finally, we ask which neuronal populations'actirity is the critical signal driring various forms of homeostatic regulation of inhibition. Using a combination of optogenetic activation and silencing strategies, we vrill determine which components of homeostatic plasticity are cell autonomous, and which depend on network actirity.
Disorders that affect the development and function of the brain including schizophrenia, autism and related diseases and epilepsy may depend critically on regulation of the balance between neuronal excitation and inhibition. A better understanding of the underlring mechanisms regulating this balance may suggest new targets for treating these important diseases.
|O'Leary, Timothy; Williams, Alex H; Franci, Alessio et al. (2014) Cell types, network homeostasis, and pathological compensation from a biologically plausible ion channel expression model. Neuron 82:809-21|