Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2^−/−) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2^−/− mice show cortical PV⁺ interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2^−/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2^−/− caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.Precursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1–3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV⁺) interneurons that tightly regulate the activity and synchronization of cortical projection neurons (2, 4). Structural and functional deficits in PV⁺ interneurons are hypothesized as a pathophysiological mechanism in schizophrenia and psychotic disorders (4–6).Although psychotic disorders are clearly heterogeneous in etiology, disinhibition within temporolimbic cortical circuits is postulated as a core pathophysiology underlying positive symptoms (e.g., delusions and hallucinations) and a subset of cognitive disturbances that manifest with psychosis (4, 5, 7). Postmortem studies of brains from individuals with psychotic disorders show reduced molecular markers of the number and/or function of PV⁺ interneurons in the hippocampus (6, 8). Consistent with these observations, basal metabolic activity in the hippocampus, as measured with functional magnetic resonance imaging (fMRI), is increased in schizophrenia, a phenotype that predicts psychosis and positive symptom severity (5, 7). This abnormal resting activity is postulated to underlie abnormal recruitment of hippocampal circuits during cognitive performance (5, 9). Striatal dopamine (DA) release capacity is also increased and correlated with positive symptoms in schizophrenia and its risk states (10, 11). Importantly, hippocampal hyperactivity may contribute to DA dysregulation (12), because rodent studies show that caudoventral hippocampal (in the primate, anterior hippocampal) efferents regulate the activity of DA neurons and medial striatal DA release (13, 14).Thus, converging evidence implicates hippocampal disinhibition in the abnormal striatal DA transmission and cognitive impairment in schizophrenia. However, the role of hippocampal inhibitory interneurons in psychosis-relevant circuitry remains to be established. To this end, we used the cyclin D2 (Ccnd2) knockout mouse model (15), which displays a relatively selective deficit in cortical PV⁺ interneurons, and transplantation of interneuron precursors from the MGE to elucidate relationships between reduced hippocampal GABA interneuron function and multiple psychosis-relevant phenotypes, and to explore a novel treatment strategy for psychosis.     

Massive isotopic effect in vacuum UV photodissociation of N2 and implications for meteorite data

Nitrogen isotopic distributions in the solar system extend across an enormous range, from −400‰, in the solar wind and Jovian atmosphere, to about 5,000‰ in organic matter in carbonaceous chondrites. Distributions such as these require complex processing of nitrogen reservoirs and extraordinary isotope effects. While theoretical models invoke ion-neutral exchange reactions outside the protoplanetary disk and photochemical self-shielding on the disk surface to explain the variations, there are no experiments to substantiate these models. Experimental results of N₂ photolysis at vacuum UV wavelengths in the presence of hydrogen are presented here, which show a wide range of enriched δ¹⁵N values from 648‰ to 13,412‰ in product NH₃, depending upon photodissociation wavelength. The measured enrichment range in photodissociation of N₂, plausibly explains the range of δ¹⁵N in extraterrestrial materials. This study suggests the importance of photochemical processing of the nitrogen reservoirs within the solar nebula.Nitrogen isotopic analyses of meteorites, terrestrial planets, atmospheres of giant planets and their moons, solar wind, comets, and interplanetary dust particles (1) may advance understanding of volatile chemistry and prebiotic processes in the early solar system.     

Anterior cruciate ligament reconstruction using hamstring autograft in over-40 patients. Does preoperative arthritic changes matter?

Introduction

The purpose of this study was to assess the effect of osteoarthritis on the outcome of arthroscopic anterior cruciate ligament (ACL) reconstruction, and to assess the effect of the procedure on the progression of osteoarthritis.

Material and methods

Forty-two patients, age above 40, presenting by symptomatic instability secondary to rupture of the ACL were enrolled in a prospective cohort study. Cases were divided into two groups according to the absence of osteoarthritic changes (group I, 19 patients) or presence of osteoarthritic changes (group II, 23 patients) in preoperative radiographs. ACL anatomic single bundle reconstruction by the anteromedial portal technique using hamstring autograft fixed by biodegradable interference fit screws was done for all patients, and a fixed postoperative rehabilitation protocol was applied. Data were recorded and statistical analysis of the preoperative, 1 year follow up, and final follow up (average 41 months in group I and 42 months in group II) results of both groups was conducted.

Results

The average patient age at the time of operation was 44.5 years in group I versus 46.4 years in group II. The follow-up median pain scores, ROM, modified Lysholm scores were significantly better in group I compared to group II. On the contrary, the difference between preoperative and 1 year postoperative scores and the percentage of improvement of the modified Lysholm score were significantly higher in group II. Deterioration of the radiographic grade of osteoarthritis in the final follow-up was declared in 15.8 % of patients of group I and in 21.7 % of patients of group II (P?=?0.71). Age, concomitant meniscus injury, and presence of preoperative arthritic changes, and cartilage defect had no statistically significantly effect on the success rate. Patients who had ACL reconstruction more than 2 years after injury and those with higher body mass index (BMI) had worse outcome than those who had earlier reconstruction and lower BMI.

Conclusion

Patients having preoperative mild to moderate arthritic changes will indeed benefit from ACL reconstruction at short term, although their overall functional outcome seemed to be inferior to the outcome of non-arthritic patients. However, osteoarthritic changes deteriorate over time in both groups especially when there is preoperative mild to moderate arthritic changes.     

Results of ACDF using Alexandria Modular Cage-Plate Construct in cervical canal stenosis

Background

The purpose of this study was to assess prospectively operative results and complications of treatment of cervical spinal canal stenosis (CCS) by anterior cervical discectomy and fusion (ACDF) using a newly introduced Alexandria Modular Cage-Plate Construct (AMCPC).

Methods

Fifteen patients (eight males, seven females) with symptomatic CCS were treated by ACDF, with a mean age of 51.2 years. Post-operative assessment depended upon clinical and radiological results.

Results

Total number of operated levels was 25 levels, with a mean 1.67 levels/patient. Mean operative time was 69.6 min/level and 116 min/patient. Average blood loss was 78 mL/level and 130 mL/patient. Mean hospital stay was 2.8 days. Post-operative dysphagia/dysphonia persisted in one patient for 1 year. One patient developed C5 radiculopathy with grade 2 deltoid weakness that recovered after 3 months. According to Odom’s criteria, results were excellent in 13 patients (86.67 %), good in 1 (6.67 %), and fair in 1 patient. In 13 patients (23 cage-plates, 92 %), the implant showed to be completely contained until the end of follow-up (24 months). One patient had a broken screw and one had screw backing-out, both did not necessitate revision. The achieved sagittal profile was maintained without sinking-in of any cage.

Conclusion

AMCPC can be used safely for a variety of disorders requiring instrumentation and fusion. It is advantageous to stand-alone cage and to rigid cage-plates when intraoperative flexibility is needed. It overcomes the disadvantages of stand-alone cage, sinking-in, cage dislodgement and post-operative rekyphosis. In addition, it obviates the need for wearing post-operative neck collar.     

Thoracoscopic interbody fusion with percutaneous posterior stabilization for thoracic and thoracolumbar injuries

Background context

Traumatic thoracolumbar discoligamentous injuries and partial burst fractures are commonly managed through posterior-only stabilization. Many cases present later with failure of posterior implant and progressive kyphotic deformities that necessitates major surgeries. Anterior interbody fusion saves the patients unnecessary long-segment fixation and provides a stable definitive solution for the injured segment.

Purpose

The purpose of this study is to assess the clinical and radiographic outcomes of combined minimal invasive short-segment posterior percutaneous instrumentation and anterior thoracoscopic-assisted fusion in thoracolumbar partial burst fractures or discoligamentous injuries.

Study design

Prospective observational study.

Patient sample

Thirty patients with acute thoracic or thoracolumbar injuries operated upon between December 2007 and January 2009.

Outcome measures

Oswestry Disability Index (ODI), clinical and neurological examination for clinical assessment. Plain X-ray for radiological evaluation.

Methods

Preoperative evaluation included clinical and neurological examination, plain X-rays, computed tomography (CT), and magnetic resonance imaging (MRI). Posterior short-segment percutaneous stabilization plus anterior thoracoscopically assisted fusion in prone position were done. The minimum follow-up period was 2 years (range 24–48 months).

Results

The mean age was 44 years. The commonest affected segment was between T10 and L1 (22 patients, 73 %). The mean total operative time was 103 min. The mean operative blood loss was 444 ml. Interbody fusion cage was used in 28 patients while iliac graft in two cases. Fusion rate at the final follow-up was 97 % (29 patients); one patient did not show definitive fusion although he was clinically satisfied. The mean final follow-up ODI was 12 %. The mean preoperative kyphosis angle was 22° improved to 6.5° postoperatively and was 7.5° at final follow-up. There were no major intraoperative or postoperative complications.

Conclusion

Combined anterior thoracoscopic fusion and short-segment posterior percutaneous instrumentation showed good clinical and radiographic outcomes in cases of thoracolumbar injuries through limiting the instrumented levels and preventing progress of posttraumatic kyphosis.