Properties of GABAergic inhibition of the medial prefrontal cortex

Gamma-aminobutyric acid type A receptors (GABAARs) are the main inhibitory neurotransmitter receptors in the central nervous system. As such, they play a pivotal role in synchronising neuronal network activity in the brain and their dysregulation has been implicated in numerous neuropsychiatric diseases such as depression, anxiety and schizophrenia. GABAARs are ligand-gated heteropentamers and can be modulated either directly or indirectly by a number of therapeutically-relevant compounds, such as the benzodiazepines, or by endogenous neuromodulators, such as the neurotransmitters dopamine and serotonin, and by neurosteroids. While much is known about the function of GABAARs, their modulation and interaction with neuromodulators and other neurotransmitter systems are less well understood. In particular, their role in the prefrontal cortex (PFC), a brain area strongly involved in motivation and planning, which is often negatively affected in neuropsychiatric disease, remains to be elucidated. The aims of this research project were to characterise synaptic and tonic inhibition in the PFC, explore dopaminergic and neurosteroid modulation of GABA inhibition and to examine effects on neuronal excitability. We focused on α2 subunit-containing GABAARs because of their role in anxiety and preferred subcellular localisation at the axon initial segment (AIS), an area that is critical for regulating neuronal spike output. Contrary to previous findings, we could not detect an effect of dopamine D4 receptor activation on GABA inhibition. However, using a mouse model expressing neurosteroid-insensitive GABAAR α2 subunits, we found evidence for a significant differential involvement of this subunit and neurosteroid modulation in GABAergic synaptic inhibition between various layers of the PFC. We discovered that alterations in phasic GABA-mediated inhibition had no significant effects on pyramidal cell excitability, whilst increasing tonic inhibition reduced cell firing. Overall, this study demonstrates that tonic GABA inhibition has a more important role to play in regulating cortical network function than previously thought

Non-Abelian pp-waves in D=4 supergravity theories

The non-Abelian plane waves, first found in flat spacetime by Coleman and subsequently generalized to give pp-waves in Einstein-Yang-Mills theory, are shown to be 1/2 supersymmetric solutions of a wide variety of N=1 supergravity theories coupled to scalar and vector multiplets, including the theory of SU(2) Yang-Mills coupled to an axion \sigma and dilaton \phi recently obtained as the reduction to four-dimensions of the six-dimensional Salam-Sezgin model. In this latter case they provide the most general supersymmetric solution. Passing to the Riemannian formulation of this theory we show that the most general supersymmetric solution may be constructed starting from a self-dual Yang-Mills connection on a self-dual metric and solving a Poisson equation for e^\phi. We also present the generalization of these solutions to non-Abelian AdS pp-waves which allow a negative cosmological constant and preserve 1/4 of supersymmetry.Comment: Latex, 1+12 page

Rotating perfect fluid sources of the NUT metric

Locally rotationally symmetric perfect fluid solutions of Einstein's gravitational equations are matched along the hypersurface of vanishing pressure with the NUT metric. These rigidly rotating fluids are interpreted as sources for the vacuum exterior which consists only of a stationary region of the Taub-NUT space-time. The solution of the matching conditions leaves generally three parameters in the global solution. Examples of perfect fluid sources are discussed.Comment: 8 pages, late

Yang's gravitational theory

Yang's pure space equations (C.N. Yang, Phys. Rev. Lett. v.33, p.445 (1974)) generalize Einstein's gravitational equations, while coming from gauge theory. We study these equations from a number of vantage points: summarizing the work done previously, comparing them with the Einstein equations and investigating their properties. In particular, the initial value problem is discussed and a number of results are presented for these equations with common energy-momentum tensors.Comment: 28 pages, to appear in Gen. Rel. Gra

SCA2 trinucleotide expansion in German SCA patients

Autosomal dominant spinocerebellar ataxias (SCA) are a group of clinically and genetically heterogeneous neurodegenerative disorders which lead to progressive cerebellar ataxia. A gene responsible for SCA type 2 has been mapped to human chromosome 12 and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. We investigated the (CAG)n repeat length of the SCA2 gene in 842 patients with sporadic ataxia and in 96 German families with dominantly inherited SCA which do not harbor the SCA1 or MJD1/SCA3 mutation, respectively. The SCA2 (CAG)n expansion was identified in 71 patients from 54 families. The (CAG)n stretch of the affected allele varied between 36 and 64 trinucleotide units. Significant repeat expansions occurred most commonly during paternal transmission. Analysis of the (CAG)n repeat lengths with the age of onset in 41 patients revealed an inverse correlation. Two hundred and forty-one apparently healthy octogenerians carried alleles between 16 and 31 repeats. One 50-year old, healthy individual had 34 repeats; she had transmitted an expanded allele to her child. The small difference between ‘normal’ and disease alleles makes it necessary to define the extreme values of their ranges. With one exception, the trinucleotide expansion was not observed in 842 ataxia patients without a family history of the disease. The SCA2 mutation causes the disease in nearly 14% of autosomal dominant SCA in Germany