Neurogenesis is important for the generation of the nervous system during embryogenesis and also for facilitating the adult hippocampal circuit plasticity involving behavioral pattern separation that transforms similar experiences into distinc memory representations (Jessberger and Gage, 2014). However, increasing adult neurogenesis after contextual learning accelerates forgetting (Ackers et al., 2014), underscoring the importance of restrained neurogenesis. The voltage-gated potassium channel Kv1.1 identified decades earlier (Tempel, Jan and Jan, 1988) is expressed not only in adulthood but also in embryogenesis (Hallows and Tempel, 1998). We conducted Mosaic Analysis with Double Markers (MADM) studies of mice heterozygous for either the Kv1.1 null mutation or the megencephaly frame shift mutation of Kv1.1 to induce somatic recombination via Nestin-cre in a few percent of neural progenitors in these seizure-free mice, and showed that loss of Kv1.1 function in neural progenitors and their progeny neurons causes an overproduction of neurons in both CA1 and the dentate gyrus (DG) of hippocampus (Yang et al., 2012). Our unexpected findings raise the possibility that Kv1.1 acts as a brake for restrained neurogenesis. To examine the role of Kv1.1 in embryonic neurogenesis and adult neurogenesis, Aim 1 will assess whether Kv1.1 function is important in regulating the proliferation of neural progenitors and/or the survival and maturation of the neurons they produce, and determine whether loss of Kv1.1 causes an increase in the number of neural progenitors during embryogenesis, while Aim 2 will determine how the loss of Kv1.1 function affects the number and proliferation of adult neural progenitors, and the survival and maturation of their progeny neurons. Finally, in Aim 3 we will examine several hypotheses for possible mechanisms underlying the action of Kv1.1 to restrain neuron production in the hippocampus. Discovery of endogenous restraint of neurogenesis by ion channels and elucidation of the underlying mechanisms will provide insight regarding how to achieve properly balanced neurogenesis. In addition, investigation of the mechanism and regulation of Kv1.1 modulation of hippocampal neurogenesis has the potential of identifying novel targets for the treatment of neurodegeneration and neuropsychiatric diseases.
Reduced neurogenesis is associated with depression, stress, and cognitive decline associated with aging, seizures, stroke, and traumatic brain injury. Moreover, whereas adult neurogenesis is important for memory formation, it has to be held in check for optimal memory retention, underscoring the importance to identify molecules and mechanisms that operate in neural progenitors to restrain neurogenesis. The proposed study is based on the discovery that the Kv1.1 voltage-gated potassium channel in neural progenitors is important for restraining neurogenesis in the hippocampus, and aims to identify the processes in neurogenesis that are under Kv1.1 regulation as well as the underlying mechanisms.
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