From synapse to behavior: rapid modulation of defined neuronal types with engineered GABAA receptors

In mammals, identifying the contribution of specific neurons or networks to behavior is a key challenge. Here we describe an approach that facilitates this process by enabling the rapid modulation of synaptic inhibition in defined cell populations. Binding of zolpidem, a systemically active allosteric modulator that enhances the function of the GABAA receptor, requires a phenylalanine residue (Phe77) in the gamma 2 subunit. Mice in which this residue is changed to isoleucine are insensitive to zolpidem. By Cre recombinase-induced swapping of the gamma 2 subunit (that is, exchanging Ile77 for Phe77), zolpidem sensitivity can be restored to GABAA receptors in chosen cell types. We demonstrate the power of this method in the cerebellum, where zolpidem rapidly induces significant motor deficits when Purkinje cells are made uniquely sensitive to its action. This combined molecular and pharmacological technique has demonstrable advantages over targeted cell ablation and will be invaluable for investigating many neuronal circuits

The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation.

AIMS/HYPOTHESIS: Defects in pancreatic beta cell turnover are implicated in the pathogenesis of type 2 diabetes by genetic markers for diabetes. Decreased beta cell neogenesis could contribute to diabetes. The longevity and turnover of human beta cells is unknown; in rodents or=90% (or=97% (>20 years) and remained constant thereafter. CONCLUSIONS/INTERPRETATION: Human beta cells, unlike those of young rodents, are long-lived. LB proportions in type 2 diabetes and obesity suggest that little adaptive change occurs in the adult human beta cell population, which is largely established by age 20 years.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

The Pak1 kinase : an important regulator of neuronal morphology and function in the developing forebrain

The mammalian central nervous system (CNS) represents a highly complex unit, the correct function of which relies on the appropriate differentiation and survival of its neurones. It is becoming apparent that the Rho family of small GTPases and their downstream targets have a major function in regulating CNS development. Among the effectors, the role of the Pak family of kinases, especially Pak1, is becoming increasingly evident. Although highest levels of Pak1 expression and activation are detected in the developing nervous system, much remains undiscovered concerning its function in neurones. This review summarises what is currently known regarding the biological and molecular role of Pak1 in the mammalian forebrain. It emphasises the importance of Pak1 in regulating neuronal polarity, morphology, migration and synaptic function. Consequently, there are also strong indications that Pak1 is required for normal cognitive function. Furthermore, loss of Pak1 has been associated with the progression of neurodegenerative disorders, particularly Alzheimer's disease, while up-regulation and de-regulation may be responsible for oncogenic transformation of support cells within the CNS, especially astrocyte progenitors. Together, these new and exciting findings encourage the future exploration into the function of Pak1 in the nervous system, thus, paving the way for novel strategies towards improved diagnosis and therapeutic treatment of diseases that affect the CNS.Peer reviewe