Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis

S1 IHC in pre-symptomatic and clinical-onset EAE: PV+ cell counts, PNN counts, and Iba-1+ microglia counts. A) Representative fluorescence photomicrographs of PV+ staining (low-mag) in S1 from control (CFA) and EAE animals at the pre-symptomatic stage (7–9 dpi PRE) or clinical onset (ONS). B) Group mean (±S.E.) total PV+ cell counts from S1HL of CFA (n = 8), PRE (n = 4), and ONS (n = 4) EAE animals. No significant differences were observed between groups (one-way ANOVA N.S.). C) Representative fluorescence photomicrographs of WFA+ staining (PNNs) in S1 from control (CFA) and EAE animals at the pre-symptomatic stage (7–9 dpi PRE) or clinical onset (ONS). D) Group mean (±S.E.) total PNN counts from S1HL of CFA (n = 11), PRE (n = 4), and ONS (n = 8) EAE animals. EAE animals exhibited significantly reduced PNN-counts vs. CFA-controls at clinical onset (one-way ANOVA, p = 0.007, post hoc comparisons vs. CFA-controls by Dunnett’s method). E) Representative fluorescence photomicrographs of Iba-1+ staining (PNNs) in S1 from control (CFA) and EAE animals at the pre-symptomatic stage (7–9 dpi PRE) or clinical onset (ONS). F) Group mean (±S.E.) total Iba-1+ counts from S1HL of CFA (n = 13), PRE (n = 4), and ONS (n = 8) EAE animals. EAE animals exhibited significantly increased numbers of Iba-1+ cells (microglial activation) in S1HL vs. CFA-controls at all time points (one-way ANOVA, p = 0.012, post hoc comparisons vs. CFA-controls by Dunnett’s method). (PDF 6418 kb

Increased sensitivity to nicotine-induced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation

ABSTRACT High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that ␣7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential ␣7 contributions, we examined ␣7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the ␣7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (ϩ/T) are viable and grow to adulthood. Hippocampal neurons from the ϩ/T mice exhibited altered ␣7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the ␣7 nAChR. We found that ϩ/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (ϩ/ϩ) littermates. Furthermore, although their behavior was normal in basal conditions, ϩ/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain ␣7 nAChR protein levels. There were no changes in the levels of ␣4, ␣5, ␣6, ␣7, ␤2, and ␤4 mRNA, or in [ 125 I]epibatidine and [ 3 H]nicotine binding between ϩ/T and ϩ/ϩ mice. Recent data from our laboratory show that ␣7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of ␣7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine

Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics

Schizophrenia is a very complex syndrome that involves widespread brain multi-dysconnectivity. Neural circuits within specific brain regions and their links to corresponding regions are abnormal in the illness. Theoretical models of dysconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. In more recent years, advancements have been achieved with the development of neuroimaging tools that have provided further clues to the structural and functional organization of the brain and global neural networks in the illness. Neural circuitry that extends across prefrontal, temporal and parietal areas of the cortex as well as limbic and other subcortical brain regions is disrupted in schizophrenia. As a result, many patients have a poor response to antipsychotic treatment and treatment failure is common. Treatment resistance that is specific to positive, negative, and cognitive domains of the illness may be related to distinct circuit phenotypes unique to treatment-refractory disease. Currently, there are no customized neural circuit-specific and targeted therapies that address this neural dysconnectivity. Investigation of targeted therapeutics that addresses particular areas of substantial regional dysconnectivity is an intriguing approach to precision medicine in schizophrenia. This review examines current findings of system and circuit-level brain dysconnectivity in treatment-resistant schizophrenia based on neuroimaging studies. Within a connectome context, on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways is discussed. Mechanistic cellular, neurochemical and molecular studies are included with specific emphasis given to cell pathology and synaptic communication in glutamatergic and GABAergic systems. In this review we attempt to deconstruct how augmenting treatments may be applied within a circuit context to improve circuit integration and treatment response. Clinical studies that have used a variety of glutamate receptor and GABA interneuron modulators, nitric oxide-based therapies and a variety of other strategies as augmenting treatments with antipsychotic drugs are included. This review supports the idea that the methodical mapping of system-level networks to both on (excitatory) and off (inhibitory) cellular circuits specific to treatment-resistant disease may be a logical and productive approach in directing future research toward the advancement of targeted pharmacotherapeutics in schizophrenia

Europe, social exclusion and the identity of social work

This paper argues that the identity of social work as a form of professional practice within Europe is a timely matter for contemporary debate. Economic and political moves in Europe towards integration have created the possibility of establishing an identity which could both incorporate a range of diverse activities and also create a form of practice that is distinct. This article will address the emerging concept of social exclusion as a potential focus for social work professional practice in a changing global setting. It will be argued that the concept is one that can incorporate the broad range of practice in social work in a manner that could have similar meaning for all the different practitioners involved