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PubMedDate not supplied

Visual evoked potentials, brainstem auditory evoked potentials, and quantitative EEG in Baltic progressive myoclonus epilepsy.

Visual and brainstem auditory evoked potentials (VEP and BAEP, respectively) and quantitative EEG were studied in 16 patients with Baltic progressive myoclonus epilepsy (PME). The study demonstrated significantly delayed VEP latencies but normal amplitudes in Baltic PME. BAEPs showed slight but significant prolongation in central conduction time. Quantitative EEG revealed diminution of beta and alpha activity and accentuation of theta and delta activity. The slowing in VEP latencies is suggested to be due to impaired synaptic transmission and to reflect dopaminergic dysfunction in Baltic PME. We conclude that there is a multimodal disturbance in sensory projections to cortical areas in Baltic PME. The results give further evidence that nondemyelinating disorders--but with synaptic transmission defects--can produce changes in evoked potentials. The changes in epileptic brain are not confined to hyperexcitable epileptic neurons, but more widespread electrophysiological phenomena are produced.

Adolescent↗
PubMed1986

Diminished interaction of norepinephrine with climbing fiber inputs to cerebellar Purkinje neurons in aged Fischer 344 rats.

The ability of norepinephrine (NE) to modulate climbing fiber activation of complex spike discharge in cerebellar Purkinje neurons was compared in young (3-6 months) and aged (18-20 months) Fischer 344 rats. In young rats, NE selectively inhibits spontaneous activity while climbing fiber evoked activity remains intact or increased. NE also increases the probability of observing 4 bursts of full-sized action potentials rather than partially inactivated action potentials in the complex spike. In older rats, both of these modulatory actions of NE on climbing fiber complex spike activation are markedly diminished. These data support the concept that age-related reductions in catecholamine modulation of synaptic inputs may contribute to CNS dysfunction found in senescence.

Aging↗
PubMed2026

Evidence supporting the role of GIGYF2 in synapse development and autism.

Autism spectrum disorder (ASD) is a heterogeneous condition in which genetically defined subtypes offered insights into underlying biological mechanisms and potential targeted treatments. Here, we investigate the clinical and pathogenic significance of GIGYF2 variants in ASD through an integrated approach combining clinical genetics, conditional knockout (cKO) mouse models, neurobiology, and molecular studies. Through targeted sequencing, large-scale genomic data analysis of neurodevelopmental disorder cohorts, and international collaborations, we identified ten affected individuals from eight families harboring de novo or dominantly inherited likely gene-disruptive (LGD) variants and 13 affected individuals from 13 families with de novo missense variants in GIGYF2. Clinical characterization of 16 probands with GIGYF2 variants revealed common features, including ASD, language problems, intellectual disability, and anxiety. In a Gigyf2 cKO mouse model, we observed pronounced autistic-like behaviors, cognitive deficits, and anxiety-like behaviors, mirroring phenotypes observed in affected individuals. Mechanistically, Gigyf2 deficiency disrupted synaptic homeostasis, as evidenced by altered spine density and miniature excitatory postsynaptic currents, and impaired IGF-1R/mTOR signaling, along with dysregulation of synapse-related genes such as Nrp2. Pharmacological inhibition of mTOR with rapamycin or Torin1, as well as Nrp2 knockdown rescued synaptic defects in Gigyf2 KO neurons. These findings define a novel ASD subtype associated with GIGYF2 variants and establish GIGYF2 as a key regulator of synaptic development and function, implicating GIGYF2 dysfunction in ASD pathogenesis and highlighting the IGF-1R/mTOR pathway as a potential therapeutic target for GIGYF2-related ASD subtype.

Journal Article↗
PubMed2026

Distinct cellular phenotypes of language and executive decline in amyotrophic lateral sclerosis.

Cognitive manifestations, including impairments in language and executive functions, are seen in amyotrophic lateral sclerosis (ALS), but the underlying mechanisms remain unclear. We mapped prefrontal cortex regions from ALS patients by integrating spatial and single-nucleus transcriptomics in a cognitively stratified patient cohort. We uncover that cognitive impairment in ALS is associated with distinct patterns of neuronal dysfunction and glial-vascular dysregulation that vary by region and cognitive subtype. Executive dysfunction is linked to reduced mitochondrial and synaptic activity in deep-layer dorsolateral prefrontal cortex neurons, whereas language-related deficits track with a diffuse pan-regional response involving glial and vascular abnormalities. Our analyses, validated by multiplexed imaging, further identify signatures in the prefrontal cortex that span both motor and cognitive phenotypes, including a multicellular gliosis response. The findings reveal that clinical heterogeneity in ALS is driven by phenotype-specific cellular interactions in motor and non-motor regions of the brain.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Mechanisms of amyloid deposition in Alzheimer's disease.

At the cellular level, Alzheimer's disease (AD) must be the result of neuronal dysfunction and degeneration leading to a reduction in synaptic density. Filamentous deposits of amyloid, which define the disease at the molecular level, occur within perikarya, axons, dendrites, and terminals of neurons as neurofibrillary tangles (NFT), in the extracellular neuropil as amyloid plaques (APC), and around blood vessels as amyloid congophilic angiopathy (ACA). These fibrillar amyloid protein aggregates are also found in the brain of all individuals with Down's syndrome after the age of 30 years. The amyloid deposits apparently occur in the terminal zones of neurons that develop NFT. It is suggested that amyloid deposition is of fundamental significance in AD and that a thorough understanding of amyloid formation will eventually lead to successful therapeutic intervention in AD. As elucidation of the reasons behind amyloid deposition must shed some light on the pathogenesis of AD, we review the current state of knowledge on the nature of the AD amyloid protein, its origin, and its formation. Although there is yet no agreement about the chemical nature of the amyloid protein of NFT, the major constituent of both APC and ACA has been shown to be a 4.5-kD amyloid protein originally termed "beta-protein" or "amyloid A4" which we now denote as "beta A4." Amyloid beta A4 protein is proteolytically derived from a transmembrane protein termed amyloid precursor protein (APP) which is encoded by a widely expressed gene on chromosome 21. Our present results are consistent with the possibility that amyloid formation requires membrane damage or APP molecules that are not or are incorrectly integrated into membranes. To allow the generation of the C-terminus of beta A4, one proteolytic cleavage step has to occur in the sequence that normally forms the transmembrane domain of the APP proteins. This cleavage is crucial for amyloid formation because we could show that the ability of synthetic beta A4 to form amyloid depositions is mainly based on hydrophobic parts of the sequence that have to interact with each other and build up large aggregates under physiologic conditions. Membrane association of APP is expected to interfere with this cleavage and the process of aggregation.

Aging↗
PubMed1988

The neurobiology of learning and memory: elucidation of the mechanisms of cognitive dysfunction.

This paper reviews evidence which suggests that there is a series of events at the synaptic level, beginning with synaptic activation, responsible for the formation of memories. Synaptic use above routine levels activates NMDA receptors which allows calcium influx into the neuron. Calcium appears to trigger changes in synapse and synaptic terminal shape (via cytoskeletal activation), and an increase in synaptic size (via new protein synthesis). New synapses ultimately form either de novo or by splitting, and new dendritic spines and dendritic length is added. Several forms of cognitive dysfunction, such as Downs syndrome, aging and Alzheimer's disease, and exposure to the neurotoxins lead or aluminum appear to involve, at least in part, disruptions in this process. Evidence is reviewed to support the theory that memories may involve alterations in specific sets of synapses located at specific dendritic locations; this theory may explain some of the learning and memory deficits seen in conditions resulting in cognitive dysfunction.

Cognition Disorders↗
PubMed1985

Substance P given intrathecally at the spinal T9 level increases adrenal output of adrenaline and noradrenaline in the rat.

Administration of 10 micrograms of substance P intrathecally to the spinal T9 level of the adult rat, anaesthetized with urethane, provoked an increase in free catecholamines in plasma taken from the inferior vena cava. Adrenaline levels at 1 min after administration were 154.8 +/- 10.8% (mean +/- SE; n = 11) of preadministration levels and noradrenaline levels were 153.5 +/- 11.8% of preadministration levels. Differences between the values of free catecholamines in animals given substance P vs those given vehicle only were statistically significant at 1 and 10 min postinjection, but not at 30 min. Administration of a substance P analogue with central antagonistic properties 15 min before substance P was given prevented expression of the effects of substance P. These results suggest that substance P may be an excitatory chemical mediator of synaptic transmission in spinal pathways controlling adrenal medullary output. Thus dysfunction of substance P mechanisms may underlie some animal models of hypertension and may be involved in some cases of essential hypertension in man as well as in autonomic dysfunction associated with some neurological entities.

Adrenal Medulla↗
PubMed1991

Diphenylhydantoin protects against hypoxia-induced impairment of hippocampal synaptic transmission.

The ability of diphenylhydantoin (DPH) to protect against hypoxia-induced neuronal damage was examined using electrophysiological recordings of extracellular evoked potentials from CA1 pyramidal neurons of rat hippocampal slices in vitro. In normal medium, a 15-min hypoxic insult (95% N2/5% CO2) produced rapid and complete loss of Schaffer collateral synaptic transmission, which only recovered to 20% of pre-hypoxia values after 90 min of reoxygenation. DPH (20 microM) bath applied prior to onset of hypoxia slowed the loss of transmission during hypoxia, and led to 75% recovery of evoked potentials upon reoxygenation. Thus, DPH appears to protect against hypoxia-induced loss of synaptic transmission, and may thereby lessen neuronal damage and cognitive dysfunction associated with stroke.

Animals↗
PubMedDate not supplied

Convergence of hippocampal and dopaminergic input onto identified neurons in the nucleus accumbens of the rat.

The hippocampal input to the nucleus accumbens was interrupted by an electrolytic lesion of the fimbria-fornix. Boutons degenerating as a result of this lesion were found in asymmetric synaptic contact with dendritic spines and shafts in the medial part of the nucleus accumbens. Dopaminergic fibres and terminals in this area, identified using an antibody to tyrosine hydroxylase, established symmetrical synaptic contacts with dendritic shafts, spines and somata. In material where neurons in the nucleus accumbens had been Golgi-impregnated, it was found that the hippocampal and dopaminergic inputs converge onto the same neurons, and that the post-synaptic targets could be either spiny or aspiny neurons. It has been suggested that hippocampal dysfunction is involved in schizophrenia and this convergence of input from the hippocampus onto the same neurons that are post-synaptic to the dopaminergic input, which presumably originates from neurons in the ventral tegmental area, may provide an anatomical basis for the therapeutic effects of neuroleptic drugs which are dopamine antagonists.

Animals↗
PubMedDate not supplied

Identification of normal and pathological aging in prospectively studied nondemented elderly humans.

Results of a standardized histochemical and immunocytochemical analysis of the brains of 14 nondemented elderly humans for whom prospective neurological and neuropsychological data had been collected for 3 to 8 years before death suggested that nondemented elderly humans fall into two pathological subgroups that are not clinically distinguishable. One was associated with moderate to marked cerebral amyloid deposition ("pathological aging"), while the other had either minimal or no amyloid deposition ("normal aging"). Neocortical and hippocampal neurofibrillary degeneration was either completely absent or of very limited degree in both subgroups. Both subgroups had ubiquitin-immunoreactive dystrophic neurites in the cerebral cortex and granular degeneration of myelin in white matter. These ubiquitin-immunoreactive structures seem to be a universal and invariant manifestation of brain aging, but the same cannot be said for amyloid deposition and neurofibrillary degeneration. Pathological aging might be preclinical Alzheimer's disease, but it currently cannot be distinguished from normal aging by even sensitive neuropsychological measures. These findings provide strong support for the hypothesis that cerebral amyloid deposition is not necessarily associated with clinically apparent cognitive dysfunction and that additional factors, such as neuronal or synaptic loss or widespread cytoskeletal aberrations, are necessary for dementia in AD.

Aged↗
PubMed1992

Abnormal isoform of prion proteins accumulates in the synaptic structures of the central nervous system in patients with Creutzfeldt-Jakob disease.

A new method, which enabled the first immunohistochemical documentation of abnormal prion protein (PrP) in all patients with Creutzfeldt-Jakob disease (CJD), was established. This method designated as "hydrolytic autoclaving" revealed punctate PrPCJD stainings around the neuronal cell bodies and dendrites in CJD brains. These punctate stainings were almost identical with that of synaptophysin, suggesting PrPCJD accumulations in the synaptic structures. Subcellular fractionation revealed that prion protein in Creutzfeldt-Jakob disease (PrPCJD) was most concentrated in the synaptosomal fraction. In CJD patients with a long clinical course, synaptophysin immunoreactivity decreased, and synaptic PrPCJD accumulated with a wider distribution. These results suggest that synaptic PrPCJD accumulations might be responsible for the neuronal dysfunction and degeneration in CJD.

Creutzfeldt-Jakob Syndrome↗
PubMed1986

Neuropathology of Rett syndrome.

Autopsy studies in 8 girls with the Rett syndrome dying between 4 and 15 years showed: Diffuse cerebral atrophy/micrencephaly, with a decrease in brain weight by 13.8 to 33.8% of age-matched controls, apparently related to the duration of the disorder; Mild, but inconsistent diffuse cortical atrophy without developmental disorders apart from occasional microdysgenesis (three cases), but increased amounts of neuronal lipofuscin, and occasional mild astrocytic gliosis; Mild, but inconsistent spongy changes in cerebral and cerebellar white matter, optic nerve (two cases), and myelinated fascicles of the brainstem tegmentum, without signs of dys- or demyelination, and apparently different from the spongy myelinopathy common to aminoacidopathies; Most conspicuous was an underpigmentation of the substantia nigra which contained many fewer well-pigmented neurons for age (53-73%), and fewer pigmented granules per neuron, while the total number of nigral neurons and the triphasic substructure of neuromelanin were normal for age. No pathologic changes were seen in locus coeruleus, nucleus basalis of Meynert, and nucleus dorsalis raphe; Electron microscopy of autopsy material from an 11-year-old girl showed increased amounts of neuronal lipofuscin without signs of a storage disorder. Reactive and degenerating axons in the caudate nucleus were possibly related to the nigral changes, suggesting some dysfunction of the dopaminergic nigro-striatal system, while the synaptic organization of the neostriatum appeared unaffected. Peripheral nerve from a patient dying in advanced stage showed increased numbers of unmyelinated (regenerated?) axons, with almost no demyelination and few remyelinated axons, suggesting axonal degeneration rather than hypomyelination, but exogenous factors (malnutrition) cannot be excluded. The pathogenetic mechanisms of the morphologic brain lesions and their relations to clinical and neurochemical findings in Rett syndrome are unknown and deserve further intensive investigations.

Adolescent↗
PubMed1987

Reduced Ca2+ flux in synaptosomes from cats with GM1 gangliosidosis.

Ca2+ transport was studied in synaptosomes prepared from normal cats and cats with GM1 gangliosidosis. The influx of Ca2+ was found to be a biphasic process in synaptosomes from both GM1 mutant and normal cats. Both the fast and slow phases of voltage-dependent Ca2+ uptake were significantly reduced in cats with the lysosomal storage disease, however the inhibitory mechanisms differed. The fast phase of Ca2+ uptake was inhibited uncompetitively, whereas the slow phase was inhibited competitively. In addition, Na+-dependent Ca2+ efflux was reduced significantly in cats with GM1 gangliosidosis. Since it is well established that maintenance of Ca2+ homeostasis is essential for normal neuronal function, a ganglioside-induced disruption of Ca2+ transport across synaptic membranes may be responsible, in part, for the neuronal dysfunction characteristic of GM1 gangliosidosis.

Animals↗
PubMed2026

Polystyrene microplastics induce auditory neurotoxicity in mammals: Integrated multi-omics profiling reveals oxidative damage and synaptic molecular dysregulation.

Microplastics (MPs) are ubiquitous environmental pollutants, yet their neurotoxic effects on the auditory system remain poorly understood. This study develops an integrated multi-level analytical framework combining auditory neurophysiology, behavioral assessment, tissue biochemistry, transcriptomics, and proteomics to investigate polystyrene (PS)-MPs-induced auditory neurotoxicity in rats. PS-MPs infiltrate the auditory system and significantly impair auditory processing, with central dysfunction emerging earlier and more prominently than peripheral alterations. Multi-omics analyses reveal coordinated suppression of glutamatergic synapse and Wnt signaling pathways in the cochlear nucleus. Mechanistically, PS-MPs perturb the crosstalk between glutamatergic synaptic and Wnt signaling, promoting AMPA receptor (AMPAR) internalization and potentially affecting synaptic plasticity-related processes and neuronal responsiveness. In parallel, PS-MPs trigger oxidative stress, apoptosis, and glial activation, reflecting pronounced neuroinflammatory and redox imbalance. In primary cochlear nucleus neurons (PCNNs), these mechanisms were further validated in vitro, where activation of Wnt signaling by Wnt3a significantly alleviated oxidative injury and reduced AMPAR internalization. Collectively, these findings provide comprehensive preclinical evidence for the neurotoxic potential of MPs and reveal a previously unrecognized PS-MPs-induced auditory neurotoxicity, although further studies are needed for human relevance. Results from the rat model further implicate Wnt-mediated signaling as a potential modulatory pathway underlying MPs-induced synaptic molecular alterations and redox dysfunction.

Animals↗
PubMed1985

[Therapy of multiple sclerosis].

The routine therapy of multiple sclerosis (MS) in world-wide use today is comprised of four measures: Antiinflammatory and antiedematous treatment with ACTH or Synacthen, respectively, and corticosteroids: only during acute episodes. - High dosage, short duration, no long-term therapy. Immunosuppression with azathioprine (Imurek): Due to the relatively high risk only to use in malignant courses (frequent and severe bouts). Basic therapy with unsaturated fatty acids (sunflower oil, Naudicelle). Influencing circumscribed target symptoms (spasticity, micturition difficulties, constipation, etc.). In addition, physiotherapeutic, psychagogic and, if necessary, nursing and social measures are included. More than a decade's experience with ultrasound therapy of the lymphatic ring as developed by Selzer in over 300 MS-patients gives the impression of a reduction in bout frequency and severity. A statistical evaluation of therapeutic efficiency has so far been impossible for well-known disease-specific reasons, which hold true for all MS-treatment methods. Great practical importance within a foreseeable space of time may be reached by efforts to influence disturbance in nerve conduction and synaptic transmission as specifically caused by the demyelination process. The successful medicinal deceleration of sodium inactivation, inhibition of potassium activation and extension of the action potential, as well as specifically influencing the neurotransmitters responsible for the disturbed synaptic transmission could lead to a total recovery or improvement of dysfunction in a great many cases. Such a "global symptomatic therapy" might indeed not change the course of disease, but bring about great progress to the patient.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Hippocampal neurobiological mechanisms of age-related memory dysfunction.

Studies are reviewed which indicate that hippocampal frequency potentiation (the growth of neural responses during repetitive synaptic stimulation) is impaired in aged rats, and that this impairment may be important in learning and memory deficits found in these aged animals. Intracellular recording and ultrastructural studies suggest that both hippocampal frequency potentiation and the age deficit in such potentiation are synaptic processes (probably presynaptic), and that the deficit may be due to an age-related increase in calcium influx during depolarization. The latter could in some way result from alterations in the function of a Ca-mediated inactivation of Ca current mechanism recently found in hippocampal neurons. Since major hippocampal changes occur with aging in both rodents and humans, it seems possible that these data are also relevant to human brain aging. Consequently, it is suggested that Alzheimer's disease results from an acceleration of normal age-related neuronal calcium conductance changes by some unknown process (e.g., viruses, aluminum, genetic factors, etc.), leading to a rapid deterioration of brain structure.

Aging↗
PubMed1989

VIP and autonomic neurotransmission.

A variety of peptides have been proposed as transmitter candidates in non-cholinergic, non-adrenergic nerves. The nerves containing vasoactive intestinal polypeptide (VIP), which innervate blood vessels, non-vascular smooth muscle, mucosal epithelium and glands comprise a major and wide-spread population of the peptide-containing systems. There is now experimental data supporting the view that VIP is a transmitter in non-adrenergic, non-cholinergic nerves in the digestive tract, respiratory tract and urogenital tract, controlling smooth muscle tone and motility, blood flow and secretion. It is possible that impairment of VIP-containing nerves is involved in a number of autonomic dysfunctions.

Animals↗