Neuronal Chloride Transporters in Health and Disease

In the past several years, there has been an exciting body of new research that links impairments in the expression or function of neuronal chloride transporters to a growing number of diseases spanning from autism to brain aging. This book introduces the core concepts and highlights the recent advances in understanding the physiology and pathophysiology of the KCC and NKCC families of neuronal chloride transporters. Neuronal chloride transporter biology is reviewed, including roles in setting the transmembrane chloride gradient and the chloride transport-independent functions, such as regulating excitatory neurotransmission. Chapters are also dedicated to addressing the structure, post-translational modification, membrane trafficking, and protein interaction partners of neuronal chloride transporters, as well as the genetic and environmental factors that regulate their expression in neurons and the novel therapeutic approaches that target neuronal chloride transporters to treat neurological diseases. This new volume will provide readers with an up-to-date summary of the recent advances in neuronal chloride transporter research, with particular emphasis on some of the key emerging topics in the field.

Autorentext
Dr. Tang is a Simons postdoctoral scholar at the Massachusetts Institute of Technology in Cambridge. As part of The Whitehead Institute for Biomedical Research, he is a member of Dr. Rudolf Jaenisch's lab, a world-renowned pioneer of transgenic science and a Whitehead founding member. His current research focus is the identification of drugs and chemical compounds that increase KCC2 expression, a neuronal chloride transporter implicated in Rett syndrome, a severe autism spectrum disorder primarily affecting young girls. He is known in the neurodevelopment field for his seminal work with human stem cell-derived neurons linking a reduction in chloride transporter expression to Rett syndrome pathogenesis, providing compelling evidence that disruptions in neuronal chloride transporters and excitation/inhibition balance may be a main cause of autism. Dr. Tang holds a position at the Simons Center for the Social Brain and holds research funds from the Rett Syndrome Research Trust.

Inhalt

1. Introduction: A historic overview of chloride transporter research

   Part I: Function of neuronal chloride transporters in regulating neuronal chloride homeostasis and brain development
   2. Methods for investigating the activities of neuronal chloride transporters

   3. The relationships between neuronal chloride transporter activities, GABAergic inhibition, and neuronal excitability
   4. Chloride transporter activities shape early brain circuit development
   5. Regulation of neuronal cell migration and cortical development by chloride transporter activities

   Part II: Function of KCC2 in regulating excitatory synapse development
   6. KCC2 regulates dendritic spine development

   7. Transport-dependent and independent functions of KCC2 at excitatory synapses
   8. KCC2 is a hub protein that balances excitation and inhibition

   Part III: The molecular and cellular biology of neuronal chloride transporters
   9. Structures of KCC and NKCC family of chloride transporters in relationship to their functions

   10. Expression pattern of neuronal chloride transporter in different brain regions and sensory organs during development
   11. Post-translational modification of neuronal chloride transporters
   12. Protein interaction partners of neuronal chloride transporters
   13. Genetic and environmental regulators of chloride transporter gene expression

   Part IV: Linking neuronal chloride transporter deficiencies to nervous system diseases
   14. The involvement of neuronal chloride transporter deficiencies in epilepsy

   15. Deficiency in chloride transporter cause cardiac and respiratory abnormalities and SUDEP
   16. Impaired chloride transporters following brain injury and cerebral palsy
   17. WNK-SPAK/OSR1-CCC Signaling in Ischemic Brain Damage
   18. The role of chloride transporters in neuropathic pain and spinal cord injury
   19. Neuronal chloride homeostasis and nerve injury
   20. Disruptions in Chloride transporters in autism spectrum disorders
   21. Chloride transporters in early brain development and Down syndrome
   22. Alterations in chloride transporter activity in stress and depression
   23. The relationships between neuronal chloride transporters, brain aging, and neurodegenerative diseases

   Part V: Development of therapies targeting neuronal chloride transporters
   24. Gene therapy approaches to restore the expression levels of Chloride transporters

   25. Utilization of NKCC1 blockers to treat brain disorders
   26. Quest for pharmacological regulators of KCC2