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At least 235 records · Page 13Linked to original sources
PubMed1994

Cholinergic denervation of the rat hippocampus by 192-IgG-saporin: electrophysiological evidence.

The consequences of intracerebroventricular injection of the toxin 192-IgG-saporin on the electrophysiological properties of CA1 pyramidal cells were investigated using intracellular recordings in the in vitro hippocampal slice preparation. We present the first electrophysiological evidence of a dysfunction of hippocampal cholinergic afferents following injection of 192-IgG-saporin. The synaptic events mediated by acetylcholine were altered in such animals: the slow cholinergic excitatory postsynaptic potentials as well as the cholinergic activation of GABAergic interneurones were dramatically depressed or even absent; the amplitude and duration of the afterhyperpolarization following a burst of spikes were increased, while other neuronal properties were not modified. These specific alterations suggest that the toxin 192-IgG-saporin is a specific tool for the experimental study of cholinergic denervation in the hippocampus.

Animals↗
PubMed2001

5-Aminolevulinic acid inhibits [3H]muscimol binding to human and rat brain synaptic membranes.

The interaction of 5-aminolevulinic acid (ALA) with GABA(A) receptors has been proposed to underlie the neurological dysfunctions of ALA-accumulating disorders, such as acute intermittent porphyria. The effects of ALA on [3H]muscimol binding to human and rat cerebral cortical membranes were compared. ALA (0.1-10 mM) significantly inhibited the binding of [3H]muscimol (12 nM), with a similar potency in rat and human membranes (IC50 = 199 vs. 228 microM, respectively). Kinetical analysis revealed that ALA (1 mM) significantly increased the Kd and decreased the Bmax of [3H]muscimol to both rat (100 and 50%, respectively) and human (200 and 40%, respectively) membranes, indicating a mixed-type inhibition. The similarity in the potency and mechanism of the ALA-induced inhibition of muscimol binding in rat and human membranes indicate that rat studies are useful to evaluate the neurotoxic properties of ALA towards the human GABAergic system, and may help to understand the pathophysiology of porphyria.

Aminolevulinic Acid↗
PubMed2003

Progressive striatal and cortical dopamine receptor dysfunction in Huntington's disease: a PET study.

We have studied the progression of striatal and extrastriatal post-synaptic dopaminergic changes in a group of 12 patients with Huntington's disease using serial (11)C-raclopride PET, a specific marker of D2 dopamine receptor binding. All patients had two (11)C-raclopride PET scans 29.2 +/- 12.8 months apart, and six of them had a third scan 13.2 +/- 3.9 months later. We found a mean annual 4.8% loss of striatal (11)C-raclopride binding potential (BP) between the first and second scans, and a 5.2% loss between the second and third scans. Statistical Parametric Mapping (SPM) localized significant baseline reductions in (11)C-raclopride BP in both striatal and extrastriatal areas, including amygdala, temporal and frontal cortex in Huntington's disease compared with normal subjects matched for age and sex. When the (11)C-raclopride scans performed 29 months after the baseline scans were considered, SPM revealed further significant striatal, frontal and temporal reductions in (11)C-raclopride BP in Huntington's disease. Cross-sectional Unified Huntington's Disease Rating Scale (UHDRS) scores correlated with (11)C-raclopride binding, but there was no correlation between individual changes in UHDRS motor scores and changes in striatal binding. Performance on all neuropsychological measures deteriorated with time but only the accuracy score of the one-touch Tower of London test correlated significantly with striatal and putamen D2 binding. In summary, serial (11)C-raclopride PET demonstrates a linear progression of striatal loss of D2 receptors in early clinically affected Huntington's disease patients over 3 years. SPM also revealed a progressive loss of temporal and frontal D2 binding. Changes over time in clinical scores and in neuropsychological assessments, except for measures of planning, did not correlate with striatal D2 binding. This probably reflects both contributions from other affected brain structures and high variance in these measures.

Adult↗
PubMed1998

Mechanisms of motor dysfunction after transient MCA occlusion: persistent transmission failure in cortical synapses is a major determinant.

BACKGROUND AND PURPOSE: Failure of prompt motor recovery after spontaneous recirculation or thrombolytic therapy may be due to an unsatisfactory restoration of synaptic activity within cortex and/or blockade of electrical impulses at the severely ischemic subcortical region. METHODS: Afferent, efferent, and synaptic activities were focally examined within the rat sensorimotor cortex by recording the somatosensory-evoked potential (SEP) and motor area response evoked by stimulation of premotor afferents (PmEP) intracortically and the motor-evoked potential (MEP) generated by stimulation of the forelimb area from the brain stem. The effect of ischemia on electrical activity in the cortex and on axonal conduction in the subcortical region was studied differentially by proximal or distal occlusion of the MCA. RESULTS: MEP consisted of direct and indirect waves generated by direct activation of pyramidal axons and indirect excitation of pyramidal neurons via cortical synapses, respectively. MEP, PmEP, and SEP disappeared on proximal occlusion. Following reperfusion after 1 to 3 hours of ischemia, the direct wave of MEP readily recovered but the indirect wave showed no improvement, suggesting a restored axonal conduction but impaired cortical synaptic transmission. The synaptic defect, which also caused a poor recovery in PmEP and SEP and on electrocorticogram, was persistent and detected 24 hours after 1 hour of proximal occlusion. CONCLUSIONS: Our data suggest that motor dysfunction is caused by loss of cortical excitability and blockade of motor action potentials at the subcortical level during ischemia. After brief transient ischemia, axonal conduction readily recovers; however, a persistent transmission failure at cortical synapses leads to motor dysfunction.

Action Potentials↗
PubMed2026

CNNM2 in schizophrenia: multilevel evidence of genetic susceptibility, magnesium homeostasis, neurodevelopment and cognitive dysfunction.

Schizophrenia (SCZ) is a common psychiatric disorder with a complex, genetically and environmentally influenced etiology, but the specific pathogenesis remains unclear. In recent years, the SCZ susceptibility gene CNNM2 (encoding cyclin M2) located at the 10q24.32-33 locus has received widespread attention. The well-validated SCZ risk interval 10q24.32-33 harbors two independent risk variants: rs11191580 in NT5C2 (significantly associated with CNNM2 mRNA and protein levels) and rs7914558 in CNNM2. Results from functional genomic analyses indicate that lower CNNM2 expression is significantly associated with SCZ. Imaging genetics studies have demonstrated that carriers of risk alleles of CNNM2 SNPs exhibit alterations in brain structure. Animal model studies have revealed that Cnnm2 downregulation in mice leads to impairments in sensorimotor gating and cognitive function. As an Mg2+ transporter, CNNM2 primarily maintains systemic Mg2+ homeostasis. According to clinical studies, a proportion of patients with SCZ exhibit reduced Mg2+ concentrations in plasma and cerebrospinal fluid. CNNM2 dysfunction may contribute to the pathology of SCZ by disrupting Mg2+ homeostasis, thereby affecting neurodevelopment and synaptic plasticity. A systematic consolidation of current evidence supporting the involvement of CNNM2 in SCZ pathogenesis provides a direction for further investigation of the pathological mechanisms underlying this disease, and for identification of novel targets for clinical intervention..

Schizophrenia↗
PubMed2002

beta-Amyloid peptide induces ultrastructural changes in synaptosomes and potentiates mitochondrial dysfunction in the presence of ryanodine.

In Alzheimer's disease (AD), loss of synapses exceeds neuronal loss and some evidence suggests a role of beta-amyloid protein (Abeta) in synaptic degeneration through a mechanism which may involve intraneuronal Ca2+ dyshomeostasis. Emerging evidence points to the participation of the internal Ca2+ stores in the pathophysiology of neurodegeneration in AD. To test the involvement of intrasynaptic Ca2+ mobilization in A toxicity, we explored the role of ryanodine receptor activation in rat cortical synaptosomes taken as a model system for the central presynapses. Evaluation of synaptosomal mitochondrial redox capacity was assessed by the MTT reduction technique, and ultrastructural changes of synaptosomes after exposure to Abeta and ryanodine were evaluated by electron microscopy. Our results show that Abeta potentiates mitochondrial dysfunction in the presence of ryanodine and induces morphological changes consisting of mitochondrial swelling and intense small synaptic vesicles depletion. These changes were accompanied by a reduction in the content of synaptophysin and actin proteins. The reduction of actin immunoreactivity was reversed in the presence of a wide range caspase inhibitors, suggesting the activation of synaptic apoptotic mechanisms.

Amyloid beta-Peptides↗
PubMed1987

Reduced uptake and release of 5-hydroxytryptamine and taurine in the cerebral cortex of epileptic El mice.

Inbred mutant El mice are highly susceptible to convulsive seizures upon 'throwing' stimulation, and the inhibition of 5-hydroxytryptamine (5-HT) and taurine activities appears to be involved in the El mouse seizures. Uptake and release of [3H]5-HT and [3H]taurine into and from cerebral neurocortical slices using a superfusion system were investigated in both non-stimulated and stimulated El mice [El(-), El(+)] and in ddY mice, which do not have a convulsive disposition. Release was defined as 40 mM K+-stimulated release. 5-HT and taurine uptake in El(+) was lower than El(-) but no difference in either uptake was found between ddY and El(-). Release of 5-HT and taurine in El(-) was higher than in ddY whereas their release in El(+) was lower than in El(-). The taurine level in the cerebral neocortex of El(-) and El(+) was higher than in ddY. These results suggest that the synaptic function of the 5-HT and taurine containing neurons is suppressed and that dysfunction of these inhibitory neurons is involved in the seizure susceptibility in the El mice.

Animals↗
PubMed2025

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Blood-Brain Barrier↗
PubMed1987

Speculations on disease states induced by excitatory amino acids.

There is much current interest in excitatory amino acids and their receptors because of their postulated involvement in several disorders of the nervous system. They function as neurotransmitters, but can act as neurotoxins in some situations. They have been implicated in the pathogenesis of cerebral hypoxic/ischemic and hypoglycemic damage, in epilepsy, in some degenerative diseases, and in some forms of neurotoxin-induced cerebral dysfunction. These diseases may reflect abnormality in a system which has evolved to provide synaptic plasticity essential for learning and memory. The purpose of this paper is to explore the ramifications of such a hypothesis.

Amino Acids↗
PubMed1999

Breakdown of calcium homeostasis in relation to tissue depolarization: comparison between gray and white matter ischemia.

In vitro studies suggest that ischemic injury of cerebral white matter is mediated by nonsynaptic cellular mechanisms, such as Ca2+ entry into axons through reversal of the Na+ -Ca2+ exchanger. The authors investigated extracellular Ca2+ concentration in relation to tissue depolarization (direct current potential) in vivo using ion-selective electrodes in cortical gray and subcortical white matter of alpha-chloralose-anesthetized cats during 120 minutes of global cerebral ischemia. On induction of ischemia, regional CBF, as measured by hydrogen clearance, ceased. The direct current potential decreased rapidly within minutes in gray matter and with little time delay in white matter. Extracellular Ca2+ concentration decreased just as quickly in gray matter. In white matter, in contrast, extracellular Ca2+ increased in the first 20 to 30 minutes, and a delayed and much slower decline, compared with gray matter, was observed thereafter, reaching a minimal level only about 60 minutes after occlusion. Our results suggest that smaller and delayed transmembrane shifts of Ca2+ are correlates of delayed ischemic membrane dysfunction in central white matter tracts, which may be explained by a lack of synaptic mechanisms.

Action Potentials↗
PubMed1992

A preliminary observation on auto-cholinergic synapse dysfunction in patients with different types of epilepsy.

Serum anti-acetylcholine receptor antibodies (A AchR Ab) and anti-synaptic premembrane antibodies (A PrM Ab) were measured in 21 patients with absence epilepsy, 21 cases with benign childhood epilepsy with centro-temporal spikes (BCECTs) and 13 cases with atypical epilepsy. Respectively, in five (23.8%), eleven (51.2%) and eight (66.7%) of the above mentioned groups of patients both A AchR Ab and A PrM Ab were found.

Adolescent↗
PubMed1989

[Intrapenile neurotransmission. Physiologic data and practical consequences].

This paper reviews the intrapenile control of erection and the principal pathophysiological and therapeutic implications (especially intracavernous injections) of these physiological data. The regulation of flaccidity is fairly well known. This principally results from a continuous adrenergic discharge responsible, via activation of the alpha receptors, for tonic contraction of the smooth muscle fibres (SMF) of the corpora cavernosa (CC), preventing blood from entering the spaces of the CC. The complementary role of serotonin, histamine, prostaglandins (PG) F1 and F2 alpha and neuropeptide Y is still unclear. The regulation of erection is less well understood. The principal phenomenon is probably inhibition of the anti-erectile alpha adrenergic tone, allowing relaxation of the SMF and congestion of the areolae of the CC, influx of arterial blood and occlusion of the venous exits. However, an additional relaxing nervous stimulation may also be required. The modulation of anti-erectile adrenergic activity could be the result of Vasoactive-Intestinal-Polypeptide which, however, is unable to induce complete erection on its own, and/or PGE1. Acetylcholine, whose role is still unclear, stimulation of beta adrenergic receptors and presynaptic alpha-2 receptors, histamine, a relaxant factor of endothelial origin and possibly other neurotransmitters as yet unidentified, may also be involved.

Alprostadil↗
PubMed1995

Clinical use of metaiodobenzylguanidine imaging in cardiology.

Cardiac function is predominantly regulated by autonomic innervation. Many heart diseases involve alterations of cardiac adrenergic neurotransmission. In patients with cardiomyopathies, numerous therapeutic agents act directly or indirectly on cardiac adrenergic disorders. Metaiodobenzylguanidine (MIBG) imaging can provide in vivo information on one of the main components of adrenergic nerve function, i.e. the norepinephrine reuptake and storage system. Diminished MIBG uptake has been reported in patients with congestive heart failure, indicating an impaired norepinephrine reuptake and storage system. In patients with dilated cardiomyopathy (either idiopathic or ischemic), this alteration has been linked to the severity of the disease, evaluated on the basis of clinical or hemodynamic parameters. Moreover, MIBG imaging has been reported in such patients to be a potent prognostic marker in comparison with other recognized indices. After myocardial infarction, the decrease in MIBG uptake was transient in some patients and was suggested to be a viability indicator. Diminished MIBG uptake in ischemic patients was linked to the occurrence of ventricular arrhythmias. In patients with primary hypertrophic cardiomyopathy, decreased cardiac MIBG uptake has also been related to the clinical indices of severity. In patients suffering from various arrhythmias such as idiopathic ventricular arrhythmias, arrhythmogenic right ventricular cardiomyopathy or a long-QT syndrome, MIBG imaging has evidenced regional abnormalities of adrenergic nerve function and has provided new insights into the pathophysiological mechanisms of such disorders. Finally, MIBG scintigraphy may permit the evaluation of anthracyclin cardiotoxicity. Thus, MIBG imaging appears to be a promising tool for the cardiologist.

3-Iodobenzylguanidine↗
PubMed1997

Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a rational approach for the development of cognition enhancers.

Activation and restoration of cholinergic function remain major foci in the development of pharmacological approaches toward the treatment of cognitive dysfunctions associated with aging and dementia. Our research has been guided by the hypothesis that (re)activation of cortical cholinergic inputs is achieved as a result of trans-synaptic disinhibition of basal forebrain cholinergic neurons. This approach depends on the ability of benzodiazepine receptor (BZR) inverse agonists to reduce the potency of GABA to block neuronal excitation. BZR inverse agonists were found to augment cortical ACh efflux through interaction with cognition-associated activation of this system. Cortical cholinergic inputs have been implicated in the processing of behaviorally significant stimuli, i.e., attentional functions. Using a recently developed and validated task for the measurement of sustained attention, or vigilance, administration of BZR inverse agonists were found to selectively increase the number of false alarms in intact animals. However, in animals with a 50-70%, but not > 90%, loss of the cortical cholinergic inputs, treatment with BZR inverse agonists alleviated the lesion-induced impairment in sustained attention and enhanced activated cortical ACh efflux. A rational development of cognitive enhancers will benefit from experiments in which cognitive and neuropharmacological variables are assessed simultaneously, thus allowing the analysis of interactions between cognition-associated neuronal activity and the neuronal and cognitive effects of putative cognition enhancers.

Acetylcholine↗
PubMed2003

Role of protein kinase A in GABAA receptor dysfunction in CA1 pyramidal cells following chronic benzodiazepine treatment.

One-week treatment with the benzodiazepine (BZ) flurazepam (FZP), results in anticonvulsant tolerance, associated with reduced GABAA receptor (GABAR) subunit protein and miniature inhibitory post-synaptic current (mIPSC) amplitude in CA1 neurons of rat hippocampus. Because protein kinase A (PKA) has been shown to modulate GABAR function in CA1 pyramidal cells, the present study assessed whether GABAR dysfunction is associated with changes in PKA activity. Two days after 1-week FZP treatment, there were significant decreases in basal (- 30%) and total (- 25%) PKA activity, and a 40% reduction in PKA RIIbeta protein in the insoluble fraction of CA1 hippocampus. The soluble component of CA1 showed a significant increase in basal (100%) but not total PKA activity. Whole-cell recording in vitro showed a 50% reduction in mIPSC amplitude in CA1 pyramidal cells, with altered sensitivity to PKA modulators. Neurons from FZP-treated rats responded to 8-bromo-cAMP with a significant increase (31%) in mIPSC amplitude. Likewise, vasoactive intestinal polypeptide (VIP), an endogenous PKA activator, caused a significant 36% increase in mIPSC amplitude in FZP-treated cells. Neither agent had a significant effect on mIPSC amplitude in control cells. This study supports a role for PKA in GABAR dysfunction after chronic FZP treatment.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1976

Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease.

Golgi and electron microscope studies of cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occur preferentially in pyramidal neurons wherein they develop between the base of the perikaryon and the initial portion of the axon. They frequently give rise to secondary neurites which bear filopodium-like processes. Meganeurites may possess spines some of which are contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development is related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibits meganeurites in juvenile GM2-hangliosidosis and Hurler's disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. It is proposed that meganeurites and meganeurite synapses contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.

Adolescent↗
PubMed1998

Evident trans-synaptic degeneration of motor neurons after stroke: a study of neuromuscular jitter by axonal microstimulation.

Neuronal degradation accompanied by axonal degeneration has been known to occur in lower motor neurons following a stroke. In the present study, the functional integrity of neuromuscular transmission was assessed, utilizing a sensitive electrodiagnostic method consisting of stimulated single-fiber electromyography (SFEMG), along with axonal microstimulation, in paralytic muscles of stroke patients. Neuromuscular jitter was measured in the hemiplegic side extensor digitorum communis (EDC) as well as in anterior tibial (AT) muscles for 28 stroke patients and also for 13 age-matched controls. The disease duration, i.e. from the onset of stroke until the stimulated SFEMG examination, extended from 2 months to 8 years. Mean jitters obtained in EDC and AT muscles of stroke patients were found to be significantly greater than those in normal controls. Mean jitters obtained in severely weak muscles of stroke patients were greater than those in moderately weak muscles. Positive correlations were noted between the increased jitter and the disease duration from the onset of stroke until the time of the stimulated SFEMG test. These findings demonstrate a dysfunction of neuromuscular transmission in the paralytic muscles of stroke patients and suggests that trans-synaptic degeneration of motor neurons may occur in stroke. Furthermore, the neuronal degradation in stroke was positively correlated with the course duration of the disease.

Aged↗