Prevalences of subclinical and overt hypothyroidism with universal screening in early pregnancy.

PURPOSE: To reveal the prevalence of subclinical and overt hypothyroidism among Turkish population during pregnancy. Also to investigate the prevalence of hypothyroidism using ATA 2017 criteria. METHODS: This is a cross-sectional study. Patients were consisted of 1416 consecutive pregnant women who were universally screened for thyroid disease in their first trimester between 2013 and 2015. Thyroid-stimulating hormone (TSH) and free T4 (FT4) levels were analyzed during the first antenatal visit (before 12 weeks of gestation). We compared different cutoffs for TSH. We further determined the 2.5th and 97.5th percentiles for TSH and FT4. RESULTS: Initially, the cutoff of 2.5 IU/ml was selected. Accordingly, 305 women (22.3%) had subclinical hypothyroidism and 22 (1.6%) was diagnosed with overt hypothyroidism. When the cutoff was increased to 4 IU/ml, only 40 (2.9%) women were diagnosed with hypothyroidism. Prevalences of overt hypothyroidism and subclinical hypothyroidism were 0.6% and 2.3%, respectively. CONCLUSION: Universal screening of pregnant women with TSH, using the 2.5 mIU/L cutoff; one in four women was found to be a candidate for thyroid hormone replacement in our cohort. When the cutoff was determined to be 4 mIU/L, prevalence of hypothyroidism decreased approximately 10 times.

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.

Energy deficit in parvalbumin neurons leads to circuit dysfunction, impaired sensory gating and social disability.

Parvalbumin-expressing, fast spiking interneurons have high-energy demands, which make them particularly susceptible to energy impairment. Recent evidence suggests a link between mitochondrial dysfunction in fast spiking cortical interneurons and neuropsychiatric disorders. However, the effect of mitochondrial dysfunction restricted to parvalbumin interneurons has not been directly addressed in vivo. To investigate the consequences of mitochondrial dysfunction in parvalbumin interneurons in vivo, we generated conditional knockout mice with a progressive decline in oxidative phosphorylation by deleting cox10 gene selectively in parvalbumin neurons (PV-Cox10 CKO). Cox10 ablation results in defective assembly of cytochrome oxidase, the terminal enzyme of the electron transfer chain, and leads to mitochondrial bioenergetic dysfunction. PV-Cox10 CKO mice showed a progressive loss of cytochrome oxidase in cortical parvalbumin interneurons. Cytochrome oxidase protein levels were significantly reduced starting at postnatal day 60, and this was not associated with a change in parvalbumin interneuron density. Analyses of intrinsic electrophysiological properties in layer 5 primary somatosensory cortex revealed that parvalbumin interneurons could not sustain their typical high frequency firing, and their overall excitability was enhanced. An increase in both excitatory and inhibitory input onto parvalbumin interneurons was observed in PV-Cox10 CKO mice, resulting in a disinhibited network with an imbalance of excitation/inhibition. Investigation of network oscillations in PV-Cox10 CKO mice, using local field potential recordings in anesthetized mice, revealed significantly increased gamma and theta frequency oscillation power in both medial prefrontal cortex and hippocampus. PV-Cox10 CKO mice did not exhibit muscle strength or gross motor activity deficits in the time frame of the experiments, but displayed impaired sensory gating and sociability. Taken together, these data reveal that mitochondrial dysfunction in parvalbumin interneurons can alter their intrinsic physiology and network connectivity, resulting in behavioral alterations similar to those observed in neuropsychiatric disorders, such as schizophrenia and autism.

Dense and overlapping innervation of pyramidal neurons by chandelier cells.

Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and thus could have an important role controlling the activity of cortical circuits. To understand their connectivity, we labeled upper layers chandelier cells (ChCs) from mouse neocortex with a genetic strategy and studied how their axons contact local populations of pyramidal neurons, using immunohistochemical detection of axon initial segments. We studied ChCs located in the border of layers 1 and 2 from primary somatosensory cortex and found that practically all ChC axon terminals contact axon initial segments, with an average of three to five boutons per cartridge. By measuring the number of putative GABAergic synapses in initial segments, we estimate that each pyramidal neuron is innervated, on average, by four ChCs. Additionally, each individual ChC contacts 35-50% of pyramidal neurons within the areas traversed by its axonal arbor, with pockets of very high innervation density. Finally, ChCs have similar innervation patterns at different postnatal ages (P18-P90), with only relatively small lateral expansions of their arbor and increases in the total number of their cartridges during the developmental period analyzed. We conclude that ChCs innervate neighboring pyramidal neurons in a dense and overlapping manner, a connectivity pattern that could enable ChCs to exert a widespread influence on their local circuits.

Losing your inhibition: linking cortical GABAergic interneurons to schizophrenia.

GABAergic interneurons of the cerebral cortex (cINs) play crucial roles in many aspects of cortical function. The diverse types of cINs are classified into subgroups according to their morphology, intrinsic physiology, neurochemical markers and synaptic targeting. Recent advances in mouse genetics, imaging and electrophysiology techniques have greatly advanced our efforts to understand the role of normal cIN function and its dysfunction in neuropsychiatric disorders. In schizophrenia (SCZ), a wealth of data suggests that cIN function is perturbed, and that interneuron dysfunction may underlie key symptoms of the disease. In this review, we discuss the link between cINs and SCZ, focusing on the evidence for GABAergic signaling deficits from both SCZ patients and mouse models.

Spatial and temporal bias in the mitotic origins of somatostatin- and parvalbumin-expressing interneuron subgroups and the chandelier subtype in the medial ganglionic eminence.

GABAergic interneurons modulate cortical activity through the actions of distinct subgroups. Recent studies using interneuron transplants have shown tremendous promise as cell-based therapies for seizure disorders, Parkinson's disease, and in the study of neocortical plasticity. Previous reports identified a spatial bias for the origins of parvalbumin (PV)- and somatostatin (SST)-expressing interneuron subgroups within the medial ganglionic eminence (MGE). In the current study, the mitotic origins of these interneurons are examined by harvesting MGE cells at 2 time points and evaluating their neurochemical profiles after transplantation into neonatal mouse cortex. Although the dorsal MGE (dMGE)-SST and ventral MGE (vMGE)-PV bias were confirmed, both subgroups originate from progenitors located throughout the MGE. The dMGE bias was also found for SST subgroups that coexpress calretinin or reelin. In contrast, another major subgroup of SST interneuron, neuropeptide Y-expressing, does not appear to originate within the MGE. Finally, novel evidence is provided that a clinically important subtype of PV-expressing interneuron, the chandelier (axo-axonic) cell, is greatly enriched in transplants from the vMGE at embryonic day 15. These findings have important implications both for the study of interneuron fate determination and for studies that use interneuron precursor transplantation to alter cortical activity.

State-dependent function of neocortical chandelier cells.

Chandelier (axoaxonic) cells (ChCs) are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells. However, their circuit role and the function of their clearly defined anatomical specificity remain unclear. Recent work has demonstrated that chandelier cells can produce depolarizing GABAergic PSPs, occasionally driving postsynaptic targets to spike. On the other hand, other work suggests that ChCs are hyperpolarizing and may have an inhibitory role. These disparate functional effects may reflect heterogeneity among ChCs. Here, using brain slices from transgenic mouse strains, we first demonstrate that, across different neocortical areas and genetic backgrounds, upper Layer 2/3 ChCs belong to a single electrophysiologically and morphologically defined population, extensively sampling Layer 1 inputs with asymmetric dendrites. Consistent with being a single cell type, we find electrical coupling between ChCs. We then investigate the effect of chandelier cell activation on pyramidal neuron spiking in several conditions, ranging from the resting membrane potential to stimuli designed to approximate in vivo membrane potential dynamics. We find that under quiescent conditions, chandelier cells are capable of both promoting and inhibiting spike generation, depending on the postsynaptic membrane potential. However, during in vivo-like membrane potential fluctuations, the dominant postsynaptic effect was a strong inhibition. Thus, neocortical chandelier cells, even from within a homogeneous population, appear to play a dual role in the circuit, helping to activate quiescent pyramidal neurons, while at the same time inhibiting active ones.

Cortical adenylyl cyclase 1 is required for thalamocortical synapse maturation and aspects of layer IV barrel development.

Experimental evidence from mutant or genetically altered mice indicates that the formation of barrels and the proper maturation of thalamocortical (TC) synapses in the primary somatosensory (barrel) cortex depend on mechanisms mediated by neural activity. Type 1 adenylyl cyclase (AC1), which catalyzes the formation of cAMP, is stimulated by increases in intracellular Ca(2+) levels in an activity-dependent manner. The AC1 mutant mouse, barrelless (brl), lacks typical barrel cytoarchitecture, and displays presynaptic and postsynaptic functional defects at TC synapses. However, because AC1 is expressed throughout the trigeminal pathway, the barrel cortex phenotype of brl mice may be a consequence of AC1 disruption in cortical or subcortical regions. To examine the role of cortical AC1 in the development of morphological barrels and TC synapses, we generated cortex-specific AC1 knock-out (CxAC1KO) mice. We found that neurons in layer IV form grossly normal barrels and TC axons fill barrel hollows in CxAC1KO mice. In addition, whisker lesion-induced critical period plasticity was not impaired in these mice. However, we found quantitative reductions in the quality of cortical barrel cytoarchitecture and dendritic asymmetry of layer IV barrel neurons in CxAC1KO mice. Electrophysiologically, CxAC1KO mice have deficits in the postsynaptic but not in the presynaptic maturation of TC synapses. These results suggest that activity-dependent postsynaptic AC1-cAMP signaling is required for functional maturation of TC synapses and the development of normal barrel cortex cytoarchitecture. They also suggest that the formation of the gross morphological features of barrels is independent of postsynaptic AC1 in the barrel cortex.

Barrel map development relies on protein kinase A regulatory subunit II beta-mediated cAMP signaling.

The cellular and molecular mechanisms mediating the activity-dependent development of brain circuitry are still incompletely understood. Here, we examine the role of cAMP-dependent protein kinase [protein kinase A (PKA)] signaling in cortical development and plasticity, focusing on its role in thalamocortical synapse and barrel map development. We provide direct evidence that PKA activity mediates barrel map formation using knock-out mice that lack type IIbeta regulatory subunits of PKA (PKARIIbeta). We show that PKARIIbeta-mediated PKA function is required for proper dendritogenesis and the organization of cortical layer IV neurons into barrels, but not for the development and plasticity of thalamocortical afferent clustering into a barrel pattern. We localize PKARIIbeta function to postsynaptic processes in barrel cortex and show that postsynaptic PKA targets, but not presynaptic PKA targets, have decreased phosphorylation in pkar2b knock-out (PKARIIbeta(-/-)) mice. We also show that long-term potentiation at TC synapses and the associated developmental increase in AMPA receptor function at these synapses, which normally occurs as barrels form, is absent in PKARIIbeta(-/-) mice. Together, these experiments support an activity-dependent model for barrel map development in which the selective addition and elimination of thalamocortical synapses based on Hebbian mechanisms for synapse formation is mediated by a cAMP/PKA-dependent pathway that relies on PKARIIbeta function.

Development of cortical maps: perspectives from the barrel cortex.

One approach to examining how higher sensory, motor, and cognitive faculties emerge in the neocortex is to elucidate the underlying wiring principles of the brain during development. The mammalian neocortex is a layered structure generated from a sheet of proliferating ventricular cells that progressively divide to form specific functional areas, such as the primary somatosensory (S1) and motor (M1) cortices. The basic wiring pattern in each of these functional areas is based on a similar framework, but is distinct in detail. Functional specialization in each area derives from a combination of molecular cues within the cortex and neuronal activity-dependent cues provided by innervating axons from the thalamus. One salient feature of neocortical development is the establishment of topographic maps in which neighboring neurons receive input relayed from neighboring sensory afferents. Barrels, which are prominent sensory units in the somatosensory cortex of rodents, have been examined in detail, and data suggest that the initial, gross formation of the barrel map relies on molecular cues, but the refinement of this topography depends on neuronal activity. Several excellent reviews have been published on the patterning and plasticity of the barrel cortex and the precise targeting of ventrobasal thalamic axons. In this review, the authors will focus on the formation and functional maturation of synapses between thalamocortical axons and cortical neurons, an event that coincides with the formation of the barrel map. They will briefly review cortical patterning and the initial targeting of thalamic axons, with an emphasis on recent findings. The rest of the review will be devoted to summarizing their understanding of the cellular and molecular mechanisms underlying thalamocortical synapse maturation and its role in barrel map formation.

Prevalence of gestational diabetes mellitus evaluated by universal screening with a 75-g, 2-hour oral glucose tolerance test and IADPSG criteria.

OBJECTIVE: To determine the prevalence of gestational diabetes mellitus (GDM) and its association with maternal age among Turkish women diagnosed by International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria. METHODS: A cross-sectional study was conducted in 2013-2015 among non-diabetic pregnant women aged 18-49 years who were universally screened for GDM by IADPSG criteria. The percentage of women meeting each diagnostic threshold and the prevalence of GDM by age group were calculated. Linear trends were evaluated by logistic regression. RESULTS: Among 1434 women screened, 159 (11.1%, 95% confidence interval 9.5%-12.7%) were diagnosed with GDM; eleven of these women had been diagnosed according to a fasting glucose level in the first trimester. The prevalence of GDM was 6.6% (10/151), 7.3% (37/507), 8.8% (42/479), 16.7% (45/270), and 35.2% (25/71) among women aged younger than 25, 25-29, 30-34, 35-39, and 40 years or older, respectively. GDM prevalence increased with age (P<0.001). The numbers of women diagnosed with GDM in the second trimester who exceeded one, two, and three thresholds of the 2-hour oral glucose tolerance test were 66 (44.6%), 52 (35.1%), and 30 (20.3%), respectively. CONCLUSION: Prevalence of GDM was correlated with maternal age. Most women diagnosed in the second trimester exceeded the threshold at only one of the three timepoints.

Spatial distribution of neurons innervated by chandelier cells.

Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and are thus thought to have an important role in controlling the activity of cortical circuits. To examine the circuit connectivity of chandelier cells (ChCs), we made use of a genetic targeting strategy to label neocortical ChCs in upper layers of juvenile mouse neocortex. We filled individual ChCs with biocytin in living brain slices and reconstructed their axonal arbors from serial semi-thin sections. We also reconstructed the cell somata of pyramidal neurons that were located inside the ChC axonal trees and determined the percentage of pyramidal neurons whose axon initial segments were innervated by ChC terminals. We found that the total percentage of pyramidal neurons that were innervated by a single labeled ChC was 18-22 %. Sholl analysis showed that this percentage peaked at 22-35 % for distances between 30 and 60 µm from the ChC soma, decreasing to lower percentages with increasing distances. We also studied the three-dimensional spatial distribution of the innervated neurons inside the ChC axonal arbor using spatial statistical analysis tools. We found that innervated pyramidal neurons are not distributed at random, but show a clustered distribution, with pockets where almost all cells are innervated and other regions within the ChC axonal tree that receive little or no innervation. Thus, individual ChCs may exert a strong, widespread influence on their local pyramidal neighbors in a spatially heterogeneous fashion.

Reduction in focal ictal activity following transplantation of MGE interneurons requires expression of the GABAA receptor α4 subunit.

Despite numerous advances, treatment-resistant seizures remain an important problem. Loss of neuronal inhibition is present in a variety of epilepsy models and is suggested as a mechanism for increased excitability, leading to the proposal that grafting inhibitory interneurons into seizure foci might relieve refractory seizures. Indeed, transplanted medial ganglionic eminence interneuron progenitors (MGE-IPs) mature into GABAergic interneurons that increase GABA release onto cortical pyramidal neurons, and this inhibition is associated with reduced seizure activity. An obvious conclusion is that inhibitory coupling between the new interneurons and pyramidal cells underlies this effect. We hypothesized that the primary mechanism for the seizure-limiting effects following MGE-IP transplantation is the tonic conductance that results from activation of extrasynaptic GABAA receptors (GABAA-Rs) expressed on cortical pyramidal cells. Using in vitro and in vivo recording techniques, we demonstrate that GABAA-R α4 subunit deletion abolishes tonic currents (Itonic) in cortical pyramidal cells and leads to a failure of MGE-IP transplantation to attenuate cortical seizure propagation. These observations should influence how the field proceeds with respect to the further development of therapeutic neuronal transplants (and possibly pharmacological treatments).

The chandelier cell, form and function.

Among γ-aminobutyric acid (GABA) interneurons, the chandelier cell (ChC) has captured the interest of neuroscientists for a very long time as a subtype not described by Ramon y Cajal. ChCs feature an axonal arborization that selectively innervates the axon initial segments of pyramidal cells. Recent studies involving transgenic mice have identified intriguing features of ChCs, including a remarkably specific spatial and temporal origins, their capacity to have either excitatory or inhibitory influences on pyramidal neurons, and their synaptic alterations in schizophrenia. This review explores these and other developmental and functional aspects of this fascinating cortical neuronal subtype.

Increased thalamocortical synaptic response and decreased layer IV innervation in GAP-43 knockout mice.

The growth-associated protein, GAP-43, is an axonally localized neuronal protein with high expression in the developing brain and in regenerating neurites. Mice that lack GAP-43 (GAP-43 -/-) fail to form a whisker-related barrel map. In this study, we use GAP-43 -/- mice to examine GAP-43 synaptic function in the context of thalamocortical synapse development and cortical barrel map formation. Examination of thalamocortical synaptic currents in an acute brain slice preparation and in autaptic thalamic neurons reveals that GAP-43 -/- synapses have larger alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR)-mediated currents than controls despite similar AMPAR function and normal probability of vesicular release. Interestingly, GAP-43 -/- synapses are less sensitive to blockade by a competitive glutamate receptor antagonist, suggesting higher levels of neurotransmitter in the cleft during synaptic transmission. Field excitatory postsynaptic potentials (EPSPs) from GAP-43 -/- thalamocortical synapses reveal a reduced fiber response, and anatomical analysis shows reduced thalamic innervation of barrel cortex in GAP-43 -/- mice. Despite this fact synaptic responses in the field EPSPs are similar in GAP-43 -/- mice and wild-type littermate controls, and the ratio of AMPAR-mediated to N-methyl-d-aspartate receptor (NMDAR)-mediated currents (AMPAR:NMDAR ratio) is larger than normal. This suggests that GAP-43 -/- mice form fewer thalamocortical synapses in layer IV because of decreased anatomical innervation of the cortex, but the remaining contacts are individually stronger possibly due to increased neurotransmitter concentration in the synaptic cleft. Together, these results indicate that in addition to its well known role in axonal pathfinding GAP-43 plays a functional role in regulating neurotransmitter release.