Apamin Improves Prefrontal Nicotinic Impairment in Mouse Model of Alzheimer's Disease.

Disruption of attention is an early and disabling symptom of Alzheimer's disease (AD). The underlying cellular mechanisms are poorly understood and treatment options for patients are limited. These early attention deficits are evident in the TgCRND8 mouse, a well-established murine model of AD that recapitulates several features of the disease. Here, we report severe impairment of the nicotinic receptor-mediated excitation of prefrontal attentional circuitry in TgCRND8 mice relative to wild-type littermate controls. We demonstrate that this impairment can be remedied by apamin, a bee venom neurotoxin peptide that acts as a selective antagonist to the SK family of calcium-sensitive potassium channels. We probe this seeming upregulation of calcium-sensitive inhibition and find that the attenuated nicotinic firing rates in TgCRND8 attention circuits are mediated neither by greater cellular calcium signals nor by elevated SK channel expression. Instead, we find that TgCRND8 mice show enhanced functional coupling of nicotinic calcium signals to inhibition. This SK-mediated inhibition exerts a powerful negative feedback on nicotinic excitation, dampening attention-relevant signaling in the TgCRND8 brain. These mechanistic findings identify a new cellular target involved in the modulation of attention and a novel therapeutic target for early attention deficits in AD.

Acute liver failure following recreational use of psychotropic "head shop" compounds.

The recreational use of the so-called "legal-highs" has been in both the medical and political arena over the last year as a result of the appearance of "head shops" in many towns in Ireland. These shops specialized in selling new psychotropic compounds that circumvented established drug legislation. Little is known about the potentially harmful effects of these substances but case reports suggest a plethora of harmful psychological and physical effects. Our case describes for the first time acute liver failure associated with the ingestion of two of these amphetamine type compounds.

Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation.

The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-d-aspartic acid (NMDA) receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by 2,5-dimethoxy-4-iodoamphetamine (DOI) (a psychedelic hallucinogen that is a partial agonist of 5-HT(2A/2C) receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a cAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor threo-beta-benzoylaspartic acid (TBOA) restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABA(A) antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia.

The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex.

Serotonin 5-HT(2A) receptors have been implicated in psychiatric illness and the psychotomimetic effects of hallucinogens. In brain slices, focal stimulation of 5-HT(2A) receptors in rat prefrontal cortex results in dramatically increased glutamate release onto layer V pyramidal neurons, as measured by an increase in "spontaneous" (nonelectrically evoked) EPSCs. This glutamate release is blocked by tetrodotoxin (TTX) and is thought to involve local spiking in thalamocortical axon terminals; however, the detailed mechanism has remained unclear. Here, we investigate parallels in EPSCs induced by either serotonin or the potassium channel blockers 4-aminopyridine (4-AP) or alpha-dendrotoxin (DTX). DTX, a selective blocker of Kv1.1-, Kv1.2-, and Kv1.6-containing potassium channels, has been shown to release glutamate in cortical synaptosomes, presumably by inhibiting a subthreshold-activated, slowly inactivating potassium conductance. By comparing DTX with other potassium channel blockers, we found that the ability to induce EPSCs in cortical pyramidal neurons depends on affinity for Kv1.2 subunits. DTX-induced EPSCs are similar to 5-HT-induced EPSCs in terms of sensitivity to TTX and omega-agatoxin-IVA (a blocker of P-type calcium channels) and laminar selectivity. The involvement of thalamocortical terminals in DTX-induced EPSCs was confirmed by suppression of these EPSCs by micro-opiates and thalamic lesions. More directly, DTX-induced EPSCs substantially occlude those induced by 5-HT, suggesting a common mechanism of action. No occlusion by DTX was seen when EPSCs were induced by a nicotinic mechanism. These results indicate that blockade of Kv1.2-containing potassium channels is part of the mechanism underlying 5-HT-induced glutamate release from thalamocortical terminals.

Serotonin induces EPSCs preferentially in layer V pyramidal neurons of the frontal cortex in the rat.

The effect of serotonin (5-HT) on the release of glutamate was examined in pyramidal cells in layers II-VI of the frontal cortex. The intracellular recording electrode contained 1% biocytin so the neurons could later be visualized with an avidin-biotin peroxidase method. Pyramidal cells in layer V of the frontal cortex showed the greatest 5-HT-induced increase in both the frequency and amplitude of 'spontaneous' (non-electrically evoked) excitatory post-synaptic currents (EPSCs). A small proportion of neurons in layer II/III showed an increase in EPSC frequency, whereas cells in layer VI showed no significant change in either EPSC frequency or amplitude. The physiological response to 5-HT mirrors the high density of 5-HT(2A) receptors in layer V, as well as the pattern of thalamic projections in frontal cortex. The specific induction of EPSCs in layer V neurons suggests that 5-HT preferentially modulates the output neurons of the frontal cortex.

Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey.

The monoaminergic innervation of cerebral cortex has long been implicated in its development. Methods now exist to examine catecholamine and serotonin inputs to identified neurons in the cerebral cortex. We have quantified such inputs on pyramidal and nonpyramidal cells in prefrontal cortex of rhesus monkeys ranging in age from 2 weeks to 10 years. Individual layer III neurons were filled with Lucifer yellow and double-immunostained with axons containing either tyrosine hydroxylase (TH) or 5-hydroxytryptamine (5-HT). The filled cells were reconstructed, and putative appositions between the axons and dendritic spines and shafts were quantified at high magnification using light microscopy. The density of catecholamine appositions on pyramidal neurons matures slowly, reaching only half the adult level by 6 months of age and thereafter rising gradually to adult levels by 2 years of age. By contrast, the density of serotonin appositions on pyramidal cells reaches the adult level before the second week after birth. The average adult pyramidal neuron in layer III of area 9m receives three times stronger input from catecholaminergic than from serotoninergic axons. The overall density of both inputs to interneurons does not appear to change during postnatal development. Selective changes in the TH innervation of pyramidal cells against a backdrop of constant TH innervation of interneurons suggest that the balance between excitation and inhibition may change developmentally in the prefrontal cortex. By contrast, 5-HT innervation of both types of neurons remains relatively constant over the age range studied.

Dyslexia, gender, and brain imaging.

Future brain imaging studies of dyslexia should have a sufficient number of males and females to detect possible gender differences in the neurological underpinning of this disorder. Detailed knowledge about such differences may clarify our understanding of the structural and functional impairments which lead to the phonological deficits that characterize dyslexia. Functional brain imaging studies have shown that males and females exhibit different patterns of brain activation during phonological processing. Further differences between the brains of males and females have been suggested by studies of normal brain development, morphology, and functional activation during reading. Animal studies have shown that lesions, similar to those seen in postmortem studies of dyslexia, affect rapid auditory processing in males, but not in females. The large body of research on gender differences in brain development, functional organization, and activation during reading tasks urges separation of males and females in dyslexia research in order to minimize variance and to detect subtle, but functionally-relevant, differences. Well-controlled studies, with large numbers of male and female dyslexics, may produce more sensitive and accurate identification of the neurological substrates of dyslexia.

MRI correlates of treatment response in first episode psychosis.

It is not known whether the magnitude of the structural brain abnormalities that underlie schizophrenia is a determinant of the extent to which patients respond to antipsychotic medication. This study was undertaken in order to explore this relationship. Twenty-six patients receiving treatment for a first episode of psychosis were involved in both a study measuring treatment response and a magnetic resonance imaging (MRI) study. In the treatment study, haloperidol dose was increased weekly beginning at 2 mg/day until patients showed evidence of a response or extrapyramidal symptoms. MRI scans were analyzed using a computerized volumetric approach to yield estimates of cerebrospinal fluid (CSF), gray-matter and white-matter volumes. Improvement in positive and negative symptoms after 1 week of treatment was significantly correlated with cortical gray-matter volumes. Those patients who were maintained on 2 mg/day of haloperidol had greater cortical gray-matter volume than those who were treated with higher doses. The severity of structural brain abnormalities at the onset of psychosis may contribute to individual variation in response to antipsychotic medication. It remains to be determined whether the degree to which particular domains of symptomatology can improve is related to the severity of structural brain pathology in specific brain regions.

Cerebral gray matter volume deficits in first episode psychosis.

BACKGROUND: Structural brain differences including decreased gray matter and increased cerebrospinal fluid volumes have been observed in the brains of chronically ill patients with schizophrenia. We hypothesized that deficits in gray matter volume would be present in patients presenting with a first episode of nonaffective psychosis. METHODS: We used magnetic resonance imaging to compare the brains of 77 patients assessed as having a first episode of psychosis (meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, or psychotic disorder not otherwise specified) with those of 61 healthy controls matched for age, sex, race, and parental socioeconomic status. Axial, dual-echo scans of the whole brain were segmented into gray matter, white matter, and cerebrospinal fluid compartments using a computerized volumetric approach. These measures were corrected for the significant effects of intracranial volume and age prior to performing between-group comparisons. RESULTS: The first episode psychosis group had significantly smaller gray matter volume (t[136] = -2.2; P = .03) and greater cerebrospinal fluid volume (t[136] = 2.5; P = .02) than normal controls. In the patient group, gray matter volumes were positively correlated with estimates of IQ but not with age of onset, duration of illness, or measures of premorbid functioning. CONCLUSIONS: Deficits in gray matter volume are present in patients experiencing first episode nonaffective psychosis. The magnitude of these differences is smaller than has been described in more chronically ill patients.

A longitudinal magnetic resonance imaging study of brain changes in adolescents with anorexia nervosa.

OBJECTIVE: To assess whether the cerebral gray and white matter volume deficits described in patients with anorexia nervosa (AN) are fully reversible with weight rehabilitation. DESIGN: A prospective cohort study using magnetic resonance imaging to examine the brains of female adolescents after weight recovery from AN. SETTING: An adolescent eating disorder program located in a tertiary care children's hospital. PARTICIPANTS: Of 13 patients who underwent a previous magnetic resonance imaging study at a low weight, 6 patients were weight recovered and underwent rescanning. All brain measures were corrected for the effects of intracranial volume and age, based on a regression analysis of a group of 34 healthy female control subjects. Scans from the patients with AN were also compared with scans from an age-matched subset of 16 healthy female controls. MAIN OUTCOME MEASURES: White matter volumes, gray matter volumes, and cerebrospinal fluid volumes in the weight-recovered AN group. RESULTS: Quantitative analysis showed that white matter and ventricular cerebrospinal fluid volumes changed significantly (P = .03 for both) on weight recovery from AN. The weight-recovered patients had significant gray matter volume deficits (P = .01) and elevated cerebrospinal fluid volumes (P = .005) compared with those of the age-matched controls. They no longer had significant (P = .30) white matter volume deficits. CONCLUSION: The finding of persistent gray matter volume deficits in patients who have recovered their weight after AN suggests an irreversible component to the structural brain changes associated with AN, in addition to a component that resolves on weight recovery.

Cerebral gray matter volume deficits after weight recovery from anorexia nervosa.

BACKGROUND: Structural changes have been observed in the brains of low-weight patients with anorexia nervosa (AN), including increased cerebrospinal fluid (CSF) volumes and decreased gray matter and white matter volumes. We hypothesized that subjects who are weight-recovered from AN would show elevated CSF volumes and reduced gray matter volumes compared with controls. METHODS: We used magnetic resonance imaging to compare the brains of 12 subjects who are weight-recovered from AN (time since weight recovery, 1-23 years) with those of 18 healthy control subjects and 13 low-weight patients with AN. Axial, dual-echo scans of the whole brain were segmented into gray matter, white matter, and CSF compartments by means of a computerized volumetric approach. Brain measures were corrected for the significant effects of intracranial volume and age, based on regression analysis of a larger group of 30 healthy female controls. RESULTS: Tests showed that the weight-recovered group had significantly greater CSF volumes and smaller gray matter volumes than the control group. By comparison with low-weight patients, the weight-recovered subjects had significantly smaller CSF volumes and significantly larger gray matter and white matter volumes. In the weight-recovered group, neither the CSF elevations nor gray matter deficits were correlated with the length of time since weight recovery. CONCLUSIONS: The persistent gray matter volume deficits in subjects who are weight-recovered from AN suggest that there may be an irreversible component to the brain changes associated with the illness. The neuropathological features of this irreversible component have yet to be characterized.

Cerebral gray matter and white matter volume deficits in adolescent girls with anorexia nervosa.

OBJECTIVES: This study was undertaken to determine whether the increased cerebrospinal fluid (CSF) volumes found in anorexia nervosa (AN) are the result of differences in gray matter or white matter volumes or both. METHODS: Thirteen adolescent girls with AN who were receiving inpatient care at a tertiary-care university children's hospital and eight healthy female control subjects were studied by using magnetic resonance imaging. Images were processed by means of software developed to classify all pixels as either CSF, gray matter, or white matter. Pixels of each class were then summed across all sections. RESULTS: The AN group had larger total CSF volumes in association with deficits in both total gray matter and total white matter volumes. Lowest reported body mass index was inversely correlated with total CSF volume and positively correlated with total gray matter volume. Urinary free cortisol levels were positively correlated with total CSF volume and inversely correlated with central gray matter volume. CONCLUSIONS: These findings add support to the view that the brain abnormalities found in AN are in large part the result of the effects of the illness. The extent to which these differences in gray matter and white matter volumes are reversible with recovery remains to be established.

Mutagenesis in mammalian cells can be modulated by radiation-induced voltage-dependent potassium channels.

In mammalian cells, little is known about the initial events whose ultimate consequence is mutagenesis or DNA repair. The role the plasma membrane may play as an initiator of such a pathway is not understood. We show, for the first time, that membrane voltage-dependent potassium (K+) currents, activated by ionizing radiation (Kuo et al., 1993), play a significant role in radiation mutagenesis. Specifically, we show that the frequency of mutation at the HGPRT locus is increased as expected to 37.6 +/- 4.0 mutations per 100,000 survivors by 800 cGy of ionizing radiation from a spontaneous frequency of 1.5 +/- 1.5. This increase, however, is abolished if either K+ channel blocker, CsCl or BaCl2, is present for 2 h following irradiation of the cells. RbCl, chemically similar to CsCl but known not to block K+ channels, is ineffective in reducing the mutation frequency. Treatment of cells with CsCl or BaCl2 had no effect on radiation-induced cell killing.