Involvement of cyclin-dependent kinase-5 in the kainic acid-mediated degeneration of glutamatergic synapses in the rat hippocampus

Increased levels of glutamate causing excitotoxic damage accompany neurological disorders such as ischemia/stroke, epilepsy and some neurodegenerative diseases. Cyclin‐dependent kinase‐5 (Cdk5) is important for synaptic plasticity and is deregulated in neurodegenerative diseases. However, the mechanisms by which kainic acid (KA)‐induced excitotoxic damage involves Cdk5 in neuronal injury are not fully understood. In this work, we have thus studied involvement of Cdk5 in the KA‐mediated degeneration of glutamatergic synapses in the rat hippocampus. KA induced degeneration of mossy fiber synapses and decreased glutamate receptor (GluR)6/7 and post‐synaptic density protein 95 (PSD95) levels in rat hippocampus in vivo after intraventricular injection of KA. KA also increased the cleavage of Cdk5 regulatory protein p35, and Cdk5 phosphorylation in the hippocampus at 12 h after treatment. Studies with hippocampal neurons in vitro showed a rapid decline in GluR6/7 and PSD95 levels after KA treatment with the breakdown of p35 protein and phosphorylation of Cdk5. These changes depended on an increase in calcium as shown by the chelators 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N ′,N′‐tetraacetic acid acetoxymethyl ester (BAPTA‐AM) and glycol‐bis (2‐aminoethylether)‐N,N,N ′,N ′‐tetra‐acetic acid. Inhibition of Cdk5 using roscovitine or employing dominant‐negative Cdk5 and Cdk5 silencing RNA constructs counteracted the decreases in GluR6/7 and PSD95 levels induced by KA in hippocampal neurons. The dominant‐negative Cdk5 was also able to decrease neuronal degeneration induced by KA in cultured neurons. The results show that Cdk5 is essentially involved in the KA‐mediated alterations in synaptic proteins and in cell degeneration in hippocampal neurons after an excitotoxic injury. Inhibition of pathways activated by Cdk5 may be beneficial for treatment of synaptic degeneration and excitotoxicity observed in various brain diseases.     

Dopamine transporter binding in females with panic disorder may vary with clinical status

Background

To date the involvement of dopamine system in neurobiology of panic disorder (PD) has been not investigated by imaging studies in humans. In this study, we evaluated the binding potential of dopamine transporter (DAT) in striatum of patients with PD.

Methods

Subjects comprised seven female patients with current PD, seven female PD patients in remission and seven female healthy controls, matched by age. Striatal DAT binding was evaluated using single-photon emission computed tomography and [¹²³I]nor-β-CIT tracer.

Results

Significantly higher DAT binding in striatum was detected in remitted PD females as compared with both currently ill PD and control females. The females with current PD demonstrated non-significant lowering in striatal DAT binding as compared with healthy controls. The correlation analysis in total sample of female patients showed significant and inverse relationship between striatal DAT binding characteristics and severity of panic symptoms.

Conclusions

This is first report showing that DAT binding in striatum may depend on the clinical status in females with PD. Our data suggest that increased level of DAT may contribute to stability of remission; however, the exact involvement of dopamine system in PD pathogenesis requires further investigations. The preliminary results of current study should be confirmed by other independent studies and should also be extended to include male patients.     

Long-term epilepsy surgery outcomes in patients with MRI-negative temporal lobe epilepsy

Purpose: The outcome of surgery in patients with temporal lobe epilepsy (TLE) and normal high‐resolution magnetic resonance imaging (MRI) has been significantly worse than in patients with unilateral hippocampal damage upon MRI. The purpose of this study was to determine the long‐term outcomes of consecutive true MRI‐negative TLE patients who all underwent standardized preoperative evaluation with intracranial electroencephalography (EEG) electrodes. Methods: In this study we present all adult MRI‐negative TLE surgery candidates evaluated between January 1990 and December 2006 at Kuopio Epilepsy Center in Kuopio University Hospital, which provides a national center for epilepsy surgery in Finland. During this period altogether 146 TLE surgery candidates were evaluated with intracranial electrodes, of whom 64 patients with normal high‐resolution MRI were included in this study. Results: Among the 38 patients who finally underwent surgery, at the latest follow‐up (mean 5.8 years), 15 (40%) were free of disabling seizures (Engel class I) and 6 (16%) were seizure‐free (Engel class IA). Twenty‐one (55%) of 38 patients had poor outcomes (Engel class III–IV). Outcomes did not change compared to 12‐month follow‐up. Histopathologic examination failed to reveal any focal pathology in 68% of our MR‐negative cases. Only patients with noncongruent positron emission tomography (PET) results had worse outcomes (p = 0.044). Discussion: Our results suggest that epilepsy surgery outcomes in MRI‐negative TLE patients are comparable with extratemporal epilepsy surgery in general. Seizure outcomes in the long‐term also remain stable. Modern imaging techniques could further improve the postsurgical seizure‐free rate. However, these patients usually require chronic intracranial EEG evaluation to define epileptogenic areas.     

Midbrain dopamine D2/3 receptor binding in schizophrenia

Several studies suggest that dysregulation of dopaminergic transmission in the midbrain and thalamus may contribute to the symptomatology of schizophrenia. The objective of this study was to examine the putative alteration of dopamine D_2/3 receptor densities in the thalamus and midbrain of drug-naïve schizophrenic patients. We used the high-affinity single-photon emission tomography ligand [¹²³I]epidepride for imaging D_2/3 receptor binding sites in six neuroleptic-naïve schizophrenic patients, and seven healthy controls. Schizophrenic symptoms were evaluated by the Positive and Negative Syndrome Scale. Significantly lower D_2/3 values were observed in the midbrain of patients with schizophrenia compared to controls (P = 0.02). No statistically significant difference was observed in the thalamus between two groups. Negative correlations were found between thalamic D_2/3 receptor binding and general psychopathological schizophrenic symptoms (r from ?0.78 to ?0.92). These observations implicate altered dopaminergic activity in the midbrain of schizophrenic patients.     

Cerebrospinal fluid insulin-like growth factors IGF-1 and IGF-2 in infantile autism

There has been little exploration of major biologic regulators of cerebral development in autism. We measured insulin-like growth factors (IGF) -1 and -2 from cerebrospinal fluid (CSF) by radio immunoassay in 25 children with autism (median age 5y 5mo; range 1y 11mo-15y 10mo; 20 males, 5 females), and in 16 age-matched comparison children without disability (median age 7y 4mo; range 1y 1mo-15y 2mo; eight males, eight females). IGF-1 and -2 concentrations were further correlated with age of patients and head size. CSF IGF-1 concentration was significantly lower in patients with autism than in the comparison group. The CSF concentrations of children with autism under 5 years of age were significantly lower than their age-matched comparisons. The head circumferences correlated with CSF IGF-1 in children with autism but no such correlation was found in the comparison group. There was no difference between the two groups in CSF IGF-2 concentrations. No patients with autism had macrocephaly. We conclude that low concentrations of CSF IGF-1 at an early age might be linked with the pathogenesis in autism because IGF-1 is important for the survival of Purkinje cells of the cerebellum. The head growth might be explained by the actions of IGF-1 and -2 reflected in CSF concentrations.     

Interaction between cholesterol and glucose metabolism during dietary carbohydrate modification in subjects with the metabolic syndrome

BACKGROUND: Carbohydrate modification based on rye bread and pasta enhances early insulin secretion in subjects with the metabolic syndrome. OBJECTIVE: Because the actions of insulin and cholesterol metabolism are interrelated, the question is raised of whether it is possible to alter cholesterol metabolism by means of dietary carbohydrate modification. DESIGN: We investigated the 12-wk effects of dietary carbohydrate modification on cholesterol synthesis and absorption by measuring the ratios of surrogate markers of precursor (cholestenol, desmosterol, and lathosterol) and absorption (cholestanol and plant sterols) sterols to cholesterol and their association to glucose metabolism in 74 subjects with the metabolic syndrome. The subjects were randomly assigned to diets with rye bread and pasta (RPa) or oat, wheat bread, and potato (OWPo) as the main carbohydrate source (34% and 37% of energy intake, respectively). RESULTS: During the study, serum cholesterol concentrations remained unchanged. Cholesterol synthesis was lower (6-10% for cholestenol and lathosterol; P < 0.05) and absorption higher (9%; P < 0.05 for sitosterol) with the OWPo diet than at baseline. With the RPa diet, cholesterol absorption was lower and synthesis higher than with the OWPo diet. The increment in the glucose area under the curve with the RPa diet was positively related to baseline cholesterol synthesis (eg, lathosterol; r = 0.480, P < 0.05) and negatively to absorption (for cholestanol; r = -0.520, P < 0.05). In the combined group, the changes in the cholestanol ratio and the insulinogenic index were interrelated (r = -0.464, P < 0.001). CONCLUSIONS: Carbohydrate modifications had dissimilar effects on cholesterol metabolism. Consumption of RPa, as compared with OWPo, may be clinically more favorable because it seems to inhibit the absorption of cholesterol, a factor crucial in the development of arterial atherosclerosis.     

Ultrafast inverse imaging techniques for fMRI

Inverse imaging (InI) supercharges the sampling rate of traditional functional MRI 10-100 fold at a cost of a moderate reduction in spatial resolution. The technique is inspired by similarities between multi-sensor magnetoencephalography (MEG) and highly parallel radio-frequency (RF) MRI detector arrays. Using presently available 32-channel head coils at 3T, InI can be sampled at 10 Hz and provides about 5-mm cortical spatial resolution with whole-brain coverage. Here we discuss the present applications of InI, as well as potential future challenges and opportunities in further improving its spatiotemporal resolution and sensitivity. InI may become a helpful tool for clinicians and neuroscientists for revealing the complex dynamics of brain functions during task-related and resting states.