In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.

Lazarus MS, Huang ZJ. Distinct maturation profiles of perisomatic and dendritic targeting GABAergic interneurons in the mouse primary visual cortex during the critical period of ocular dominance plasticity. J Neurophysiol 106: 775-787, 2011. First published May 25, 2011 doi:10.1152/jn.00729.2010In the rodent primary visual cortex, maturation of GABA inhibitory circuitry is regulated by visual input and contributes to the onset and progression of ocular dominance (OD) plasticity. Cortical inhibitory circuitry consists of diverse groups of GABAergic interneurons, which display distinct physiological properties and connectivity patterns. Whether different classes of interneurons mature with similar or distinct trajectories and how their maturation profiles relate to experience dependent development are not well understood. We used green fluorescent protein reporter lines to study the maturation of two broad classes of cortical interneurons: parvalbumin-expressing (PV) cells, which are fast spiking and innervate the soma and proximal dendrites, and somatostatin-expressing (SOM) cells, which are regular spiking and target more distal dendrites. Both cell types demonstrate extensive physiological maturation, but with distinct trajectories, from eye opening to the peak of OD plasticity. Typical fast-spiking characteristics of PV cells became enhanced, and synaptic signaling from PV to pyramidal neurons became faster. SOM cells demonstrated a large increase in input resistance and a depolarization of resting membrane potential, resulting in increased excitability. While the substantial maturation of PV cells is consistent with the importance of this source of inhibition in triggering OD plasticity, the significant increase in SOM cell excitability suggests that dendrite-targeted inhibition may also play a role in OD plasticity. More generally, these results underscore the necessity of cell type-based analysis and demonstrate that distinct classes of cortical interneurons have markedly different developmental profiles, which may contribute to the progressive emergence of distinct functional properties of cortical circuits.

Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.

Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PVGAD67+/−) or in all interneurons (GABAGAD67+/−) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PVGAD67+/− mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABAGAD67+/− mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell typespecificity of the GAD67 deficit, failed to provide proof-of-concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor.

Background: Atypical manifestations of COVID-19 are being encountered as the pandemic unfolds, leading to non-chest CT scans that may uncover unsuspected pulmonary disease.Purpose: To investigate patients with primary non-respiratory symptoms who underwent abdomen/pelvis or cervical spine/neck CT with unsuspected findings highly suspicious for pulmonary COVID-19. three institutions, two in a region considered a hotspot (area of high prevalence) for COVID-19. Patients without known COVID-19 were included who presented to the emergency room (ER) with primary non-respiratory [gastrointestinal (GI) or neurological] symptoms, had lung parenchymal findings suspicious for COVID-19 on a non-chest CT but no concurrent chest CT and had COVID-19 testing in the ER. Group 1 patients had RT PCR obtained pre-CT read (COVID-19 suspected on presentation); Group 2 had RT PCR obtained post-CT read (COVID-19 not suspected). Presentation and imaging findings were compared and outcomes were evaluated. Descriptive statistics and Fisher exact tests were used for analysis.Results: Group 1 comprised 62 patients [31 men, 31 women, mean age 67(SD ±17) years] and group 2 comprised 57 patients [28 men, 29 women, mean age 63(SD ± 16) years). Cough and fever were more common in group 1 (37/62, 60%, 29/62, 47%) than group 2

Background Levels of cannabinoid 1 receptor (CB1R) mRNA and protein, which are expressed most heavily in the cholecystokinin class of GABA neurons, are lower in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia, and the magnitude of these differences is strongly correlated with that for glutamic acid decarboxylase (GAD67) mRNA, a synthesizing enzyme for GABA. However, whether this correlation reflects a cause-effect relationship is unknown. Methods Using quantitative in situ hybridization, we measured CB1R, GAD67, and diacylglycerol lipase alpha (DAGLα; the synthesizing enzyme for the endocannabinoid 2-arachidonoylglycerol) mRNA levels in the medial prefrontal cortex of genetically-engineered GAD67 heterozygous (GAD67+/−), CB1R heterozygous (CB1R+/−), CB1R knockout (CB1R−/−), and matched wild-type mice. Results In GAD67+/− mice, GAD67 and CB1R mRNA levels were significantly reduced by 37% and 16%, respectively, relative to wild-type mice and were significantly correlated across animals (r=0.61; p=0.01). In contrast, GAD67 mRNA levels were unaltered in CB1R+/− and CB1R−/− mice. Expression of DAGLα mRNA, which is not altered in schizophrenia, was also not altered in any of the genetically-engineered mice. Conclusions The findings that reduced GAD67 mRNA expression can induce lower CB1R mRNA expression support the hypothesis that lower cortical levels of CB1Rs in schizophrenia may partially compensate for deficient GAD67-mediated GABA synthesis by reducing endogenous cannabinoid suppression of GABA release.

Background: Image guidance for spine pain control procedures, including epidural steroid injection, nerve root block, and facet block, can be performed with either computed tomography (CT) or conventional fluoroscopy. CT has the advantage of improved anatomic localization and use of air for contrast; however, there are concerns that CT leads to higher radiation dose and longer procedure time. Objective: To evaluate procedure time and radiation dose for multiple types of spine pain control procedures performed under CT guidance. Study Design: Retrospective evaluation. Setting: Department of radiology in single academic medical center. Methods: Institutional review board approval was obtained. We reviewed CT-guided spine procedures performed over a 12-month period from January 2012 to December 2012. Procedure type, procedure time, and dose-length product were recorded. Patient age and gender were recorded for each case; additionally, demographic and medical history data were obtained for a sub-group of patients. Results: Nine hundred ninety-four studies (performed in 699 patients) were reviewed, including 585 epidural steroid injections, 228 nerve root blocks, and 90 facet blocks. For all studies, procedure time averaged 7:34 ± 5:05, and dose-length product averaged 75 mGy·cm ± 61. Additional medical history (available for 483 patients) revealed high rate of obesity (body mass index [BMI] = 30 ± 6.8, with 76% of patients overweight [BMI > 25] and 42% obese [BMI > 30]), and frequent medical comorbidities (including hypertension [n = 179], diabetes [n = 101], renal failure [n = 30], and heart failure [n = 17]). Limitations: This study was performed retrospectively, and limited to a single institution. Conclusion: These findings add to the growing evidence that CT guidance is a safe and effective technique for epidural steroid injection. These results further demonstrate that other spine intervention procedures, including nerve root block and facet block, can also be performed under CT guidance with short procedure time and reasonable levels of radiation exposure. This approach can be effectively used in a patient population with a high rate of obesity and medical comorbidities. Key words: Epidural steroid injection, nerve root block, facet block, CT-guidance, spine intervention, radiation dose

Lemierre's syndrome is an acute oropharyngeal infection with a secondary septic thrombophlebitis of the internal jugular vein (IVJ) that was first reported in literature in 1936. It involves the progression of disease from a focal suppurative peritonsillar infection to a local septic thrombophlebitis with hematogenous progression to and distant septic emboli. It is a rare and potentially fatal syndrome requiring prompt diagnosis and management. We present the case progression of an 18-year-old male who presented to our hospital with resolved sore throat, fever, and chest discomfort who experienced a sharp clinical decline. His case, physical exam, laboratory abnormalities, and radiologic studies highlight important facets of this rare but important syndrome.