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.

Summarizes roles of KCCs and NKCCs in regulating inhibitory and excitatory neurotransmissionReviews the molecular and cellular biology of neuronal chloride transportersLinks neuronal chloride transporter deficiencies to autism, epilepsy, depression, and moreIdentifies role of transporter deficiencies in pain as well as brain and spinal cord injuryDiscusses drug research targeting neuronal chloride transporters for nervous system diseases

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