Potential Airborne Releases and Deposition of Radionuclides from the Santa Susana Field Laboratory during the Woolsey Fire.

ABSTRACT: The Santa Susana Field Laboratory (SSFL), located in southern California, is a former research facility, and past activities have resulted in residual radioactive contamination in Area IV of the Site. The Woolsey Fire burned across the site, including some of the contaminated areas, on 8-11 November 2018. Atmospheric transport modeling was performed to determine where the smoke plume went while the fire burned across the SSFL and the deposition footprint of particulates in downwind communities. Any radionuclides on vegetation and in surface soil released by the fire were assumed to follow particulate matter transport path and deposition. The predicted deposition footprint was used to guide confirmatory soil sampling at 16 locations including background. Highest offsite deposition was determined to be northeast of the Oak Park community, which is located about 6 km southwest of SSFL. Depth-profile sampling was used to evaluate whether radionuclides of SSFL origin were potentially emitted and deposited during the Woolsey Fire. If radionuclides had been deposited from the Woolsey Fire at sufficient concentrations, then they would be detected in the surface layer and would be expected to be higher within the plume footprint than outside it. An upper bound estimate of the hypothetical effective dose to a person in Oak Park based on measured radionuclide concentrations in soil and vegetation on the SSFL was less than 0.0002 mSv. The occurrence of naturally occurring radionuclides at concentrations above the established background for the SSFL was attributed to natural variability in geologic formations and not SSFL. No anthropogenic radionuclides were measured at levels above those expected from global fallout. The soil sampling confirmed that no detectable levels of SSFL-derived radionuclides migrated from SSFL at the locations sampled because of the Woolsey Fire or from past operations of the SSFL.

Dosimetry associated with veterans who participated in nuclear weapons testing.

BACKGROUND: This article summarizes the methodology, results, and challenges of the reconstruction of red bone marrow and male breast doses for a 1982-person sub-cohort of ∼114,270 U.S. military veterans who participated in eight atmospheric nuclear weapons tests between 1945 and 1962. These doses are being used in an epidemiological investigation of leukemia and male breast cancer as part of a study of one million U.S. persons to investigate risk from chronic low-dose radiation exposure. METHODS: Previous doses to these veterans had been estimated for compensation and tended to be biased high but newly available documentation made calculating individual doses and uncertainties using detailed exposure scenarios for each veteran possible. The techniques outlined in this report detail the methodology for developing individual scenarios and accounting for bias and uncertainty in dose based on the assumptions made about exposure. RESULTS: Doses to the atomic veterans in this sub-cohort were relatively low, with about two-thirds receiving red bone marrow doses <5 mGy and only four individuals receiving a red bone marrow dose >50 mGy. The average red bone marrow dose for members of the sub-cohort was 5.9 mGy. Doses to male breast were approximately 20% higher than red bone marrow doses. DISCUSSION AND CHALLENGES: Relatively low uncertainty was achieved as a result of our methodology for reconstructing exposures based on knowledge of the individual veterans' locations and activities from military records. Challenges did arise from use of military records to determine probability of participation in specific activities but accounted for in estimates of uncertainty.

Asbestos exposure and mesothelioma mortality among atomic veterans.

BACKGROUND: The United States (U.S.) conducted 230 above-ground atmospheric nuclear weapons tests between 1945 and 1962 involving over 250,000 military personnel. This is the first quantitative assessment of asbestos-related mesothelioma, including cancers of the pleura and peritoneum, among military personnel who participated in above-ground nuclear weapons testing. METHODS: Approximately 114,000 atomic veterans were selected for an epidemiological study because they were in one of eight series of weapons tests that were associated with somewhat higher personnel exposures than the other tests and because they have been previously studied. We were able to categorize specific jobs into potential for asbestos exposure based on a detailed database of the military activities of the atomic veterans. Standardized mortality ratios (SMR) were calculated by service, rank (officer/enlisted) and ratings (occupation code and work location aboard ship) after 65 years of follow-up. RESULTS: Mesothelioma deaths were significantly increased overall (SMR 1.56; 95% CI 1.32-1.82; n = 153). This increase was seen only among those serving in the PPG (SMR 1.97; 95% CI 1.65-2.34; n = 134), enlisted men (SMR 1.81; 95% CI 1.53-2.13; n = 145), and the 70,309 navy personnel (SMR 2.15; 95% CI 1.80-2.56; n = 130). No increased mortality rates were seen among the other services: army (SMR 0.45), air force (SMR 0.85), or marines (SMR 0.75). Job categories with the highest potential for asbestos exposure (machinist's mates, boiler technicians, water tender, pipe fitters, and fireman) had an of SMR 6.47. Job categories with lower potential (SMR =1.35) or no potential (SMR =1.28) for asbestos exposure had non-significantly elevated mesothelioma mortality. CONCLUSIONS: The large excess of mesothelioma deaths seen among atomic veterans was explained by asbestos exposure among enlisted naval personnel. The sources of exposure were determined to be on navy ships in areas (or with materials) with known asbestos content. No excess of mesothelioma was observed in other services or among naval personnel with minimal exposure to asbestos in this low-dose radiation exposed cohort.

Analysis of Environmental Data to Support Quantification of Historical Releases from a Former Uranium Processing Facility in Apollo, Pennsylvania.

ABSTRACT: This paper describes how environmental measurement data were used to help quantify the spatial impact and behavior of uranium released to the environment from a uranium manufacturing facility in Apollo, PA. The Apollo facility released enriched uranium to the environment while it operated between 1957 and 1983. Historical monitoring data generated by the site, along with other independent data sources, provided a long-term record documenting the presence and behavior of uranium in the local environment. This record of evidence, together with reconstructed estimates of facility releases, has been used to estimate environmental concentrations during facility operations and potential exposures to members of the public. Historical environmental measurement data were also used to confirm predictions of deposition and concentrations in air. The data are used here to derive atmospheric deposition velocities for the uranium emissions. Based on the spatial pattern of measurements and calculated deposition velocities around the facility, the released material contained larger particles that deposited close to the facility, and the released material remains largely in the surface layers of the soil, indicating limited downward mobility. Evidence of measurable impacts was determined to extend a relatively short distance (<500 m) from the facility. The soil data collected around Apollo are also compared to findings related to uranium mobility at another facility where uranium was released to the environment, and similar behavior was observed at both sites.

Reconstruction of Enriched Uranium Released to Air from the Former Apollo Facility, Apollo, Pennsylvania.

ABSTRACT: The former Apollo facility converted enriched uranium hexafluoride into uranium oxide for shipment to nuclear fuel fabrication plants from 1957 to 1983. This paper describes quantification of the source term from the Apollo facility in terms of quantities of uranium released, particle size, and solubility characteristics. Releases occurred through stacks, rooftop vents, and an incinerator that operated from 1964 to 1969. Incidental and accidental releases are addressed as part of this analysis. Atmospheric releases of uranium from plant operations were estimated from stack sampling and production records. Roof vents, both filtered and unfiltered, were the major emission points from the plant. The total estimated release of uranium activity (including 234U, 235U, and 238U) to the air was 28 GBq. Measurements by others found that the releases were primarily associated with large particles and that their solubility was variable but generally low (Class Y). The release estimates presented here and those findings were incorporated into a sophisticated atmospheric transport model to estimate atmospheric concentrations and soil contamination levels due to the releases and to reconstruct historical doses to individuals that lived in the vicinity of the former Apollo facility.

Reconstruction of atmospheric concentrations of enriched uranium from the former Apollo facility, Apollo, Pennsylvania, USA.

The former Apollo facility in western Pennsylvania converted enriched uranium hexafluoride into uranium oxide for shipment to nuclear fuel fabrication plants from 1957 to 1983. Atmospheric releases of uranium from plant operations were estimated from stack sampling and production records. Releases occurred through stacks, rooftop vents, and an incinerator that operated from 1964 to 1969. Roof vents that exhausted workplace air was the major emission source from the plant. Total estimated release of uranium activity (including 234U, 235U, and 238U) to the air was 27.9 GBq. Atmospheric transport modeling was performed using a complex terrain model because the plant was located in an incised river valley. Almost two years of meteorological data were collected from a nearby 10-m tower, along with sounding from a collocated sodar. Light mean wind speed (1.56 m s-1) and predominately stable atmospheric conditions frequently resulted in poor dispersion conditions in the facility environs. Environmental sampling included continuous air monitoring data and depth profiles of uranium in soil that was deposited from airborne releases. Soil measurements exhibited a sharp drop-off in uranium concentrations with distance from the facility, indicating that large non-inhalable particles were emitted to the atmosphere. Large particles (~15-25 µm aerodynamic equivalent diameter) accounted for 17.5% of the total emissions. Soil measurements were used for model calibration and validation, while air measurements were used to evaluate model performance. Air concentrations were generally over-predicted for locations near the facility but showed only a slight positive bias for locations north of the facility. Predicted uranium activity air concentrations from Apollo sources averaged over 34 years were about three times greater than the background gross alpha activity value of 81 µBq m-3 in a ~0.5 km2 region surrounding the Apollo facility. The contribution of Apollo uranium to the gross alpha air concentration would have been negligible several kilometers from the facility.

Use of Routine Environmental Monitoring Data to Establish a Dose-based Compliance System for a Low-level Radioactive Waste Disposal Site.

A dose-based compliance methodology was developed for Waste Control Specialists, LLC, low-level radioactive waste facility in Andrews, Texas, that allows routine environmental measurement data to be evaluated not only at the end of a year to determine regulatory compliance, but also throughout the year as new data become available, providing a continuous assessment of the facility. The first step in the methodology is a screening step to determine the potential presence of site emissions in the environment, and screening levels are established for each environmental media sampled. The screening accounts for spatial variations observed in background for soil and temporal fluctuations observed in background for air. For groundwater, the natural activity concentrations in groundwater wells at the facility are highly variable, and therefore the methodology uses ratios for screening levels. The methodology compares the ratio of gross alpha to U + U to identify potentially abnormal alpha activity and the ratio of U to U to identify the potential presence of depleted uranium. Compliance evaluation is conducted for any samples that fail the screening step. Compliance evaluation uses the radionuclide-specific measurements to first determine (1) if the dose exceeds the background dose and if so, (2) the dose consequences, so that the appropriate investigation or action occurs. The compliance evaluation is applied to all environmental samples throughout the year and on an annual basis to determine regulatory compliance. The methodology is implemented in a cloud-based software application that is also made accessible to the regulator. The benefits of the methodology over the existing system are presented.

The immunohistochemical distribution of the GABAA receptor α1, α2, α3, ß2/3 and γ2 subunits in the human thalamus.

The GABAA receptor is the most abundant inhibitory receptor in the human brain and is assembled from a variety of different subunit subtypes which determines their pharmacology and physiology. To determine which GABAA receptor subunit proteins are found in the human thalamus we investigated the distribution of five major GABAA receptor subunits α1, α2, α3, ß2,3 and γ2 using immunohistochemical techniques. The α1-, ß2,3- and γ2- subunits which combine to form a benzodiazepine sensitive GABAA receptor showed the most intense levels of staining and were the most common subunits found throughout the human thalamus especially in the ventral and posterior nuclear groups. The next most intense staining was for the α3-subunit followed by the α2-subunit. The intralaminar nuclear group, the mediodorsal nucleus and the thalamic reticular nucleus contained α1-, ß2,3- and γ2- subunits staining as well as the highest levels of the α2- and α3- subunits. The sensory dorsal lateral geniculate nucleus contained very high levels of α1- and ß2,3- and γ2-subunits. The highest densities of GABAA receptors found throughout the thalamus which contained the subunits α1, ß2,3, and γ2 included nuclei which are especially involved in the control or the modulation of the cortico-basal ganglia-thalamo-cortical motor circuits and are thus important in disorders such as Huntington's disease where the GABAergic projections of the basal ganglia are compromised. In addition the majority of receptors in the thalamic reticular nucleus contain α3 and γ2 subunits whilst the intralaminar nuclei contain high levels of α2 and α3 subunits.

Red Bone Marrow and Male Breast Doses for a Cohort of Atomic Veterans.

Both red bone marrow and male breast doses with associated uncertainty have been reconstructed for a 1,982-person subset of a cohort of 114, 270 military personnel (referred to as "atomic veterans") who participated in U.S. atmospheric nuclear weapons testing from 1945 to 1962. The methods used to calculate these doses and corresponding uncertainty have been reported in detail by Till et al. in an earlier publication. In this current article we report the final results of those calculations. These doses are being used in a case-cohort design epidemiological investigation of leukemia and male breast cancer. This cohort of atomic veterans is one component in a broader-scope study of approximately one million U.S. persons designed to investigate risk from chronic low-dose radiation exposure. Doses to the atomic veterans in this sub-cohort were relatively low, with approximately two-thirds receiving red bone marrow doses <5 mGy and only four individuals receiving a red bone marrow dose >50 mGy. The average red bone marrow dose for members of the sub-cohort was 5.9 mGy. Doses to male breast were approximately 20% higher than red bone marrow doses. The uncertainty in the estimated doses was relatively low, considering relevant personnel dosimetry was available for only about 25% of the subjects, and most of the doses were reconstructed from film badges worn by co-workers or from the individual's military record and military unit activities. The average coefficient of variation for the individual dose estimates was approximately 0.5, comparable to the uncertainty in doses estimated for the Japanese A-bomb survivors. Although the reconstructed red bone marrow doses were about 36% lower on average than the conservative doses previously estimated by the military for compensation, the overall correlation was quite good, suggesting that the estimates of doses from external exposure by the military for all ∼115,000 cohort members could be adjusted appropriately and used in further epidemiological analyses.

Military participants at U.S. Atmospheric nuclear weapons testing--methodology for estimating dose and uncertainty.

Methods were developed to calculate individual estimates of exposure and dose with associated uncertainties for a sub-cohort (1,857) of 115,329 military veterans who participated in at least one of seven series of atmospheric nuclear weapons tests or the TRINITY shot carried out by the United States. The tests were conducted at the Pacific Proving Grounds and the Nevada Test Site. Dose estimates to specific organs will be used in an epidemiological study to investigate leukemia and male breast cancer. Previous doses had been estimated for the purpose of compensation and were generally high-sided to favor the veteran's claim for compensation in accordance with public law. Recent efforts by the U.S. Department of Defense (DOD) to digitize the historical records supporting the veterans' compensation assessments make it possible to calculate doses and associated uncertainties. Our approach builds upon available film badge dosimetry and other measurement data recorded at the time of the tests and incorporates detailed scenarios of exposure for each veteran based on personal, unit, and other available historical records. Film badge results were available for approximately 25% of the individuals, and these results assisted greatly in reconstructing doses to unbadged persons and in developing distributions of dose among military units. This article presents the methodology developed to estimate doses for selected cancer cases and a 1% random sample of the total cohort of veterans under study.

An integrated approach to data management, risk assessment, and decision making.

This paper describes a methodology called Risk Analysis, Communication, Evaluation, and Reduction (RACER) that converts environmental data directly to human health risk to enhance decision making and communication. The methodology was developed and implemented following the Cerro Grande fire in New Mexico that burned approximately 7,500 acres of Los Alamos National Laboratory in May 2000. The absence of a coordinated and comprehensive approach to managing and understanding environmental data was a major weakness in the responding agencies' ability to make and communicate decisions. RACER consists of three basic elements: managing information, converting information to knowledge, and communicating knowledge to decision makers and stakeholders. Data are maintained in a web-accessible database that accepts data as they are validated and uploaded. The user can select data for evaluation and convert them to knowledge using human health risk as a benchmark for ranking radionuclides, chemicals, pathways, or other criteria needed to make decisions. Knowledge about risk is communicated using graphic and tabular formats. The process is transparent, flexible, and rapid, which enhances credibility and trust among decision makers and stakeholders. The fundamental principles used in RACER can be applied anywhere radionuclides or chemicals are present in the environment.

RACER: dynamic use of environmental measurement data for decision making and communication.

To facilitate access to and use of environmental measurement data, Risk Assessment Corporation has developed a data management system as part of its Risk Analysis, Communication, Evaluation, and Reduction process. The concepts of data consistency are not new, but many data management applications are developed around managing the entire data life cycle, rather than on using the data to reach meaningful conclusions. The RACER process is specifically focused on the efficient use of available data to promote sound decision making. The RACER data management system provides a means of understanding trends in data, comparing data to frequently referenced comparison values, and organizing environmental measurement data for use by other components of the RACER process that evaluate human health impacts. Data transfers to the system can be automated to occur frequently for facilities collecting large volumes of data to achieve a dynamic point of access to measurement data that reflects the most recently available information. Because the RACER process is designed around the most common uses of data, its utility spans a broad range of potential applications, from routine monitoring and reporting to emergency response decision making based on potential human health impacts. Because it is portable and flexible, the elements of the system can be used in any situation where there is a need to efficiently access and interpret environmental measurement data. Its output and functions are equally relevant for small datasets with hundreds of measurements or large and complex datasets with millions of measurements.

Differential localization of gamma-aminobutyric acid type A and glycine receptor subunits and gephyrin in the human pons, medulla oblongata and uppermost cervical segment of the spinal cord: an immunohistochemical study.

Gephyrin is a multifunctional protein responsible for the clustering of glycine receptors (GlyR) and gamma-aminobutyric acid type A receptors (GABA(A)R). GlyR and GABA(A)R are heteropentameric chloride ion channels that facilitate fast-response, inhibitory neurotransmission in the mammalian brain and spinal cord. We investigated the immunohistochemical distribution of gephyrin and the major GABA(A)R and GlyR subunits in the human light microscopically in the rostral and caudal one-thirds of the pons, in the middle and caudal one-thirds of the medulla oblongata, and in the first cervical segment of the spinal cord. The results demonstrate a widespread pattern of immunoreactivity for GlyR and GABA(A)R subunits throughout these regions, including the spinal trigeminal nucleus, abducens nucleus, facial nucleus, pontine reticular formation, dorsal motor nucleus of the vagus nerve, hypoglossal nucleus, lateral cuneate nucleus, and nucleus of the solitary tract. The GABA(A)R alpha(1) and GlyR alpha(1) and beta subunits show high levels of immunoreactivity in these nuclei. The GABA(A)R subunits alpha(2), alpha(3), beta(2,3), and gamma(2) present weaker levels of immunoreactivity. Exceptions are intense levels of GABA(A)R alpha(2) subunit immunoreactivity in the inferior olivary complex and high levels of GABA(A)R alpha(3) subunit immunoreactivity in the locus coeruleus and raphe nuclei. Gephyrin immunoreactivity is highest in the first segment of the cervical spinal cord and hypoglossal nucleus. Our results suggest that a variety of different inhibitory receptor subtypes is responsible for inhibitory functions in the human brainstem and cervical spinal cord and that gephyrin functions as a clustering molecule for major subtypes of these inhibitory neurotransmitter receptors.

Altered mnemonic functions and resistance to N-METHYL-d-Aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1.

Converging evidence from pharmacological and molecular studies has led to the suggestion that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-d-aspartate receptor (NMDAR) activity by increasing the extra-cellular concentration of glycine in the vicinity of glutamatergic synapses. However, the precise extent and limitation of this approach to alter cognitive function, and therefore its potential as a treatment strategy against psychiatric conditions marked by cognitive impairments, remain to be fully examined. Here, we generated mutant mice lacking GlyT1 in the entire forebrain including neurons and glia. This conditional knockout system allows a more precise examination of GlyT1 downregulation in the brain on behavior and cognition. The mutation was highly effective in attenuating the motor-stimulating effect of acute NMDAR blockade by phencyclidine, although no appreciable elevation in NMDAR-mediated excitatory postsynaptic currents (EPSC) was observed in the hippocampus. Enhanced cognitive performance was observed in spatial working memory and object recognition memory while spatial reference memory and associative learning remained unaltered. These findings provide further credence for the potential cognitive enhancing effects of brain GlyT1 inhibition. At the same time, they indicated potential phenotypic differences when compared with other constitutive and conditional GlyT1 knockout lines, and highlighted the possibility of a functional divergence between the neuronal and glia subpopulations of GlyT1 in the regulation of learning and memory processes. The relevance of this distinction to the design of future GlyT1 blockers as therapeutic tools in the treatment of cognitive disorders remains to be further investigated.

Differential localization of GABAA receptor subunits within the substantia nigra of the human brain: an immunohistochemical study.

Gamma-aminobutyric acid(A) (GABA(A)) receptors (GABA(A)R) are inhibitory heteropentameric chloride ion channels comprising a variety of subunits and are localized at postsynaptic sites within the central nervous system. In this study we present the first detailed immunohistochemical investigation on the regional, cellular, and subcellular localisation of alpha(1), alpha(2), alpha(3), beta(2,3), and gamma(2) subunits of the GABA(A)R in the human substantia nigra (SN). The SN comprises two major regions, the SN pars compacta (SNc) consisting of dopaminergic projection neurons, and the SN pars reticulata (SNr) consisting of GABAergic parvalbumin-positive projection neurons. The results of our single- and double-labeling studies demonstrate that in the SNr GABA(A) receptors contain alpha(1), alpha(3), beta(2,3), and gamma(2) subunits and are localized in a weblike network over the cell soma, dendrites, and spines of SNr parvalbumin-positive nonpigmented neurons. By contrast, GABA(A)Rs on the SNc dopaminergic pigmented neurons contain predominantly alpha(3) and gamma(2) subunits; however there is GABA(A)R heterogeneity in the SNc, with a small subpopulation (6.5%) of pigmented SNc neurons additionally containing alpha(1) and beta(2,3) GABA(A)R subunits. Also, in the SNr, parvalbumin-positive terminals are adjacent to GABA(A)R on the soma and proximal dendrites of SNr neurons, whereas linear arrangements of substance P-positive terminals are adjacent to GABA(A) receptors on all regions of the dendritic tree. These results show marked GABA(A)R subunit hetereogeneity in the SN, suggesting that GABA exerts quite different effects on pars compacta and pars reticulata neurons in the human SN via GABA(A) receptors of different subunit configurations.

Hippocampal alpha 5 subunit-containing GABA A receptors are involved in the development of the latent inhibition effect.

Hippocampal GABA(A) receptors containing the alpha 5 subunit have been implicated in the modulation of hippocampal-dependent learning, presumably via their tonic inhibitory influence on hippocampal glutamatergic activity. Here, we examined the expression of latent inhibition (LI)--a form of selective learning that is sensitive to a number of manipulations targeted at the hippocampal formation, in alpha 5(H105R) mutant mice with reduced levels of hippocampal alpha 5-containing GABA(A) receptors. A single pre-exposure to the taste conditioned stimulus (CS) prior to the pairing of the same CS with LiCl-induced nausea was effective in reducing the conditioned aversion against the taste CS in wild-type mice--thus constituting the LI effect. LI was however distinctly absent in male alpha 5(H105R) mutant mice. Hence, a partial loss of hippocampal alpha 5 GABA(A) receptors is sufficient to alter one major form of selective learning, albeit this was not seen in the female. This observed phenotype suggests that specific activation of these extrasynaptic GABA(A) receptors may confer therapeutic potential against the failure to show selectivity in learning by human psychotic patients.

GABA(A) receptor diversity and pharmacology.

Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.

A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction.

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.

Pathophysiology and pharmacology of GABA(A) receptors.

By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in brain function. GABAergic interneurons are highly diverse. The respective GABA(A) receptor subtypes, therefore, provide new opportunities not only for understanding GABA-dependent pathophysiologies but also for targeting of selective neuronal circuits by drugs. The pharmacological relevance of GABA(A) receptor subtypes is increasingly being recognized. A new central nervous system pharmacology is on the horizon. The development of anxiolytic drugs devoid of sedation and of agents that enhance hippocampus-dependent learning and memory has become a novel and highly selective therapeutic opportunity.

Hippocampal alpha5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition.

Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5(H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.