Schizophrenia
can be partially characterized by deficits in sensory processing. Biochemical,
molecular, and genetic studies of one such endophenotype, the P50
auditory-evoked potential gating ...deficit, suggest that one of the neuronal
nicotinic receptors, the α7 nicotinic receptor, may function in an
inhibitory neuronal pathway involved in this phenotype. The P50 deficit is
normalized in nongating subjects by nicotine. Although most schizophrenia
patients are heavy smokers, the effects of nicotine may be transient, as
α7 receptors are known to desensitize rapidly. In an animal model of
the P50 gating deficit, antagonists of the α7 nicotinic receptor block
normal gating of the second of paired auditory stimuli. Regional localization of
receptor expression includes areas known to function in sensory filtering. An
inhibitory mechanism, in the hippocampus, may involve nicotinic stimulation of
γ-amino-butyric acid (GABA)ergic interneurons, resulting in decreased
response to repetitive stimuli. Expression of the α7 receptor is
decreased in hippocampal brain tissue, dissected postmortem, from schizophrenia
subjects. The P50 deficit is inherited in schizophrenia pedigrees, but it is not
sufficient for disease development and thus represents a predisposition factor.
Linkage analysis between the P50 deficit in multiplex schizophrenia pedigrees
and deoxyribonucleic acid (DNA) markers throughout the genome yielded positive
lod scores to DNA markers mapping to a region of chromosome 15 containing the
α7 nicotinic receptor gene. Elucidation of possible interactions of the
P50 with other factors, known to be important in the etiology of the disease, is
important in determining an overall pathobiology of schizophrenia.
Ethanol increases miniature inhibitory postsynaptic current frequency and decreases the paired-pulse ratio, which suggests that ethanol increases both spontaneous and evoked GABA release, ...respectively. We have shown previously that ethanol increases GABA release at the rat interneuron-Purkinje cell synapse and that this ethanol effect involves calcium release from internal stores; however, further exploration of the mechanism responsible for ethanol-enhanced GABA release was needed. We found that a cannabinoid receptor 1 (CB1) agonist, WIN-55212, and a GABA(B) receptor agonist, baclofen, decreased baseline spontaneous GABA release and prevented ethanol from increasing spontaneous GABA release. The CB1 receptor and GABA(B) receptor are Galpha i-linked G protein-coupled receptors with common downstream messengers that include adenylate cyclase and protein kinase A (PKA). Adenylate cyclase and PKA antagonists blocked ethanol from increasing spontaneous GABA release, whereas a PKA antagonist limited to the postsynaptic neuron did not block ethanol from increasing spontaneous GABA release. These results suggest that presynaptic PKA plays an essential role in ethanol-enhanced spontaneous GABA release. Similar to ethanol, we found that the mechanism of the cannabinoid-mediated decrease in spontaneous GABA release involves internal calcium stores and PKA. A PKA antagonist decreased baseline spontaneous GABA release. This effect was reduced after incubating the slice with a calcium chelator, BAPTA-AM, but was unaffected when BAPTA was limited to the postsynaptic neuron. This suggests that the PKA antagonist is acting through a presynaptic, calcium-dependent mechanism to decrease spontaneous GABA release. Overall, these results suggest that PKA activation is necessary for ethanol to increase spontaneous GABA release.
Whereas ethanol has behavioral actions consistent with increased GABAergic function, attempts to demonstrate a direct enhancement of GABA-gated currents by ethanol have produced mixed results. Recent ...work has suggested that a part of the GABAergic profile of ethanol may result from enhanced GABA release from presynaptic terminals. The present study examines the effect of ethanol on GABA release in several brain regions to assess the regional nature of ethanol-induced GABA release. Whole-cell voltage clamp recording of spontaneous inhibitory postsynaptic currents (sIPSCs) from mechanically dissociated neurons and miniature inhibitory postsynaptic currents (mIPSCs) and paired-pulse ratio (PPR) from a slice preparation were used to quantify GABA release. Ethanol produced a concentration-dependent increase in the frequency of sIPSCs recorded from mechanically dissociated cerebellar Purkinje neurons and mIPSCs from substantia nigra neurons without having an effect on sIPSCs recorded from lateral septal or cerebrocortical neurons. This regional difference in the effect of ethanol on GABA release was confirmed with PPR recording from brain slices. These data indicate that ethanol can act on presynaptic terminals to increase GABA release in some brain regions while having little or no effect on GABA release in others. This regional difference is consistent with earlier in vivo studies in which ethanol affected neural activity and sensitivity to GABA in some, but not all, brain sites.
The blood–brain barrier is the main obstacle to efficient delivery of therapeutic reagents, including viral vectors, into the central nervous system (CNS) for treating global CNS diseases. In this ...study, the effects of mannitol infusions on global brain gene expression of a novel AAV vector were examined after intravenous (iv) or intracisternal injection. Initially, a self-complementary adeno-associated virus serotype 2 vector (scAAV) was compared to traditional single-stranded AAV2 vector for reporter gene expression in the brain of adult mice with or without pretreatment of an iv mannitol infusion. One to two months postinjection, analysis of vector-transduced green fluorescent protein (GFP) expression in the brain revealed that vector delivery to the CNS via iv injection required pretreatment with mannitol. This expression was observed only when scAAV vectors were used. Using these conditions, transgene expression was observed in various neurons and glial cells throughout the brain. The peripherally administered scAAV vectors also transduced the cells in multiple somatic tissues with efficient expression in liver (20–30% of hepatocytes), but was less efficient in other somatic tissues. Intracisternal injection of scAAV vector produced a broad and intense transgene expression in both neurons and glial cells in the CNS of injected mice ranging from the olfactory area to the brain stem and spinal cord. More than 50% of the Purkinje cells in the cerebellum expressed GFP. Intravenous infusion of mannitol before intracisternal injection of the scAAV vector enhanced the dispersion of the vector in the CNS. Further optimization of these steps combining peripheral and intracisternal scAAV gene delivery should facilitate the development of treatments for global CNS diseases, especially diseases involving both the somatic system and the CNS, such as lysosomal storage disorders.
Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes due to chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor ...T-cell (CART) therapy, is FDA approved for relapsed or refractory (R/R) B-ALL in patients <25 years; however, the safety and efficacy of this therapy in young patients is largely unknown since children <3 years of age were excluded from licensing studies.
We retrospectively evaluated data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n=14). Sixty-four percent of patients (n=9) achieved minimal residual disease (MRD)-negative remission post-CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) were refractory to this therapy (n=5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥ grade 3 cytokine release syndrome. No neurotoxicity was reported.
This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.
Chronic nicotine administration in animal models evokes a dose-dependent increase in brain nicotinic receptor numbers. Genetically determined variability in nicotinic receptor number in different ...mouse strains has also been reported, which is thought to affect sensitivity to nicotine, as well as the development of tolerance. Humans self-administer nicotine principally in the form of cigarettes and other tobacco products. The present study compared 3Hnicotine binding in human postmortem brain from thalamus and hippocampus of nonsmoking subjects, subjects who had variable life-long smoking histories and subjects who had quit smoking. A significant increase was seen in 3Hnicotine binding in both hippocampus and thalamus of subjects with life-long smoking histories. In the hippocampus, this change resulted from a change in total receptor number (Bmax), with no change in receptor affinity (Kd). There was also a positive correlation between the degree of smoking, as measured by the average reported packs smoked per day, and the number of nicotine binding sites found in both the hippocampus and thalamus, showing that humans exhibit a dose-dependent increase in brain nicotinic receptor binding. Receptor levels in these brain regions after smoking cessation were at or below those found in the control population, which indicated that smoking-induced changes are reversible after cessation of nicotine treatment. These results suggest that increases in nicotinic receptor levels in the human brain may underlie nicotine tolerance and addiction in smokers.
A variety of fluent and nonfluent aphasias have been reported after left basal ganglia stroke. It has been speculated that this heterogeneity may reflect variations in cortical hypoperfusion ...resulting from large vessel stenosis. To test this hypothesis, a consecutive series of 24 patients with left caudate infarct identified with diffusion-weighted imaging underwent language testing and perfusion-weighted imaging <24
h from onset of symptoms. Specific regions in perisylvian cortex were rated for the percentage of the region that was hypoperfused. Aphasia type was determined on the basis of speech fluency, comprehension, and repetition performance on the language tests. Association between aphasia type/language impairment and regions of hypoperfusion were identified with Fisher’s exact tests. Results demonstrated that in patients with acute left caudate infarct, the presence and type of aphasia reflected regions of hypoperfusion, and generally followed predictions based on chronic lesion studies, regarding anatomical lesions associated with classic aphasia types.
Basis of the Gabamimetic Profile of Ethanol Breese, G. R.; Criswell, H. E.; Carta, M. ...
Alcoholism, clinical and experimental research,
04/2006, Volume:
30, Issue:
4
Journal Article
Peer reviewed
Open access
This article summarizes the proceedings of a symposium held at the 2005 Research Society on Alcoholism meeting. The initial presentation by Dr. Wallner provided evidence that selected GABAA receptors ...containing the δ subunit display sensitivity to low intoxicating ethanol concentrations and this sensitivity is further increased by a mutation in the cerebellar α6 subunit, found in alcohol‐hypersensitive rats. Dr. Mameli reported that ethanol affects γ‐aminobutyric acid (GABA) function by affecting neural circuits that influence GABA release. Dr. Parsons presented data from electrophysiological and microdialysis investigations that ethanol is capable of releasing GABA from presynaptic terminals. Dr. Morrow demonstrated that systemic ethanol increases neuroactive steroids in brain, the absence of which alters various functional responses to ethanol. Dr. Criswell presented evidence that the ability of ethanol to increase GABA was apparent in some, but not all, brain regions indicative of regional specificity. Further, Dr. Criswell demonstrated that neurosteroids alone and when synthesized locally by ethanol act postsynaptically to enhance the effect of GABA released by ethanol in a region specific manner. Collectively, this series of reports support the GABAmimetic profile of acutely administered ethanol being dependent on several specific mechanisms distinct from a direct effect on the major synaptic isoforms of GABAA receptors.
Recent data have demonstrated that ethanol increases gamma-aminobutyric acid (GABA) release in many brain regions, but little is known about the mechanism responsible for this action. Consistent with ...previous results, ethanol increased miniature inhibitory postsynaptic current (mIPSC) frequency at the interneuron-Purkinje cell synapse in the slice and in mechanically dissociated neurons. These data suggest that ethanol is increasing spontaneous GABA release at this synapse. It is generally accepted that ethanol increases levels of intracellular calcium and that changes in intracellular calcium can alter neurotransmitter release. Therefore, we examined the contribution of calcium-dependent pathways to the effect of ethanol on spontaneous GABA release at the interneuron-Purkinje cell synapse. Ethanol continued to increase mIPSC frequency in a nominally calcium-free extracellular solution and in the presence of a voltage-dependent calcium channel inhibitor, cadmium chloride. These data suggest that influx of extracellular calcium does not play a critical role in the mechanism of ethanol-enhanced spontaneous GABA release. However, a sarco/endoplasmic-reticulum calcium ATPase pump inhibitor (thapsigargin), an inositol 1,4,5-trisphosphate receptor antagonist (2-aminoethoxydiphenylborate) and a ryanodine receptor antagonist (ryanodine) significantly reduced the ability of ethanol to increase mIPSC frequency. In addition, ethanol was still able to increase mIPSC frequency in the presence of intracellular 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and a cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251); thus, retrograde messengers are not involved in ethanol-enhanced spontaneous GABA release. Overall, these data suggest that calcium release from presynaptic internal stores plays a vital role in the mechanism of ethanol-enhanced spontaneous GABA release at the interneuron-Purkinje cell synapse.
Abstract While research on the actions of ethanol at the GABAergic synapse has focused on postsynaptic mechanisms, recent data have demonstrated that ethanol also facilitates GABA release from ...presynaptic terminals in many, but not all, brain regions. The ability of ethanol to increase GABA release can be regulated by different G protein-coupled receptors (GPCRs), such as the cannabinoid-1 receptor, corticotropin-releasing factor 1 receptor, GABAB receptor, and the 5-hydroxytryptamine 2C receptor. The intracellular messengers linked to these GPCRs, including the calcium that is released from internal stores, also play a role in ethanol-enhanced GABA release. Hypotheses are proposed to explain how ethanol interacts with the GPCR pathways to increase GABA release and how this interaction contributes to the brain region specificity of ethanol-enhanced GABA release. Defining the mechanism of ethanol-facilitated GABA release will further our understanding of the GABAergic profile of ethanol and increase our knowledge of how GABAergic neurotransmission may contribute to the intoxicating effects of alcohol and to alcohol dependence. Research Highlights ► Ethanol facilitates GABA release in some, but not all, brain regions. ► Different GPCRs regulate ethanol-enhanced GABA release. ► Intracellular messengers alter the ability of ethanol to increase GABA release.
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