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PubMed2005

Synaptic differences in the postmortem striatum of subjects with schizophrenia: a stereological ultrastructural analysis.

The striatum processes motor, cognitive, and limbic function, all of which are perturbed in schizophrenia. The present study examined the synaptic organization of the caudate and putamen in schizophrenia. Postmortem striatum was obtained from 10 normal controls (NC) and 17 subjects with schizophrenia (SZ), prepared for electron microscopy, and analyzed using stereological principles. The densities of total synapses, asymmetric synapses (characteristic of excitatory inputs), and asymmetric axospinous synapses (characteristic of cortical input) were higher in the caudate of the SZs vs. NCs. These changes were most profound in the off-drug SZ cases and were also elevated in subjects on antipsychotic drugs (APDs). In comparison to NCs, there were no significant differences in the putamen of the SZ cohort as a whole group; however, there were more asymmetric axospinous synapses in the off-drug subgroup. The increase in density of synapses in the SZs does not appear to be caused by antipsychotic medication and may represent failure of normal synaptic pruning or abnormal sprouting. Higher density of cortical-type synapses in SZs vs. NCs may reflect adaptation of corticostriatal circuitry or hyperstimulation of striatal projection neurons. The abnormal synaptic organization could have several important and different downstream effects depending on the precise circuitry involved and may be related to limbic or cognitive dysfunction in schizophrenia.

Adult↗
PubMed2005

The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia.

The pathogenesis of schizophrenia may be ascribed to early maldevelopment of brain tissue. Neurotrophins are a group of dimeric proteins that affect the development of the nervous system in all vertebrates' species. Since neurotrophins, as well as other growth factors, play a crucial role in neurodevelopment, they are plausible candidates of taking part in the pathophysiology of schizophrenia. In line with this hypothesis, accumulating preclinical and clinical data indicate that dysfunctions of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may contribute to impaired brain development, neuroplasticity and synaptic "dysconnectivity" leading to the schizophrenic syndrome, or at least some of its presentations. This article reviews the functions of neurotrophins in the complex process of normal brain development, and their possible relevance to the neuropathology and neuropharmacology of schizophrenia. Further research in this area may bring about novel pharmacological therapeutic strategies to this chronic debilitating disorder.

Animals↗
PubMed2003

Mutation and association analysis of the DAP-1 gene with schizophrenia.

Glutamate dysfunction has been hypothesized to be involved in the pathophysiology of schizophrenia. The human homolog of Drosophila discs large protein (hDLG) and post-synaptic density-95-associated protein-1 (DAP-1) is one of the major proteins that are involved in intracellular signal transduction via N-methyl-d-aspartate receptors. In the present study 33 Japanese patients with schizophrenia were screened for mutations in the DAP-1 gene. A single nucleotide polymorphism was identified in the DAP-1 gene (1618A/G). A case-control study using a larger sample of unrelated patients and controls did not reveal a significant association between this polymorphism and schizophrenia. The results do not provide evidence that the DAP-1 gene is involved in vulnerability to schizophrenia.

Case-Control Studies↗
PubMed2002

The inner hair cell afferent/efferent synapses revisited: a basis for new therapeutic strategies.

Within the cochlea, the sensory inner hair cells, which transduce the mechanical displacement of the basilar membrane into neural activity, release glutamate that acts on postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor channels located on dendrites of primary auditory neurons. Up to now, it has been thought that the auditory nerve responses passively reflected the motion of the basilar membrane supporting the organ of Corti. Here, we show that dopaminergic lateral olivocochlear efferents drive a permanent gain control at the site of auditory action potential initialization. A dysfunction of this system leads to the development of early signs of excitotoxicity. With the knowledge of the molecular mechanisms involved at this first synaptic complex in the cochlea, it is now possible to envisage local treatments for spiral ganglion neurons, either to stop an excitotoxically induced hyperexcitability (probably the starting point of most posttraumatic tinnitus) or to prevent neuronal death (neural presbycusis).

Animals↗
PubMed1990

Approaches for the development of oral drug therapies for erectile dysfunction.

Currently, there are no effective oral drug therapies for the treatment of sexual dysfunction. The intent of this review was to outline the new research strategies that have emanated from experimental and clinical observations. These strategies include pharmacologic modification of cellular responses within the ventral diencephalon, brain stem, spinal cord, and penis, which represent segments of the erectile response systems. Although it is theoretically possible to treat sexual dysfunction by targeting any one of these segments, a single approach would most likely benefit only a subgroup of patients. Erectile dysfunction patients may have characteristics of several disorders, in which case combined drug therapies may be more useful. The goal of the current research is to define the regulation of sexual function at each segment of the response loop and to apply this knowledge to the treatment of the diverse disorders that contribute to erectile dysfunction.

Animals↗
PubMed2003

Short-term cerebral ischemia causes the dysfunction of interneurons and more excitation of pyramidal neurons in rats.

Neural excitotoxicity is a typical factor in the early phase pathogenesis of cerebral ischemia. Its cellular and molecular mechanisms are still unclear and clinical approaches are still lacking of promising therapies. We have examined the vulnerability of cortical neurons to short-term ischemia in rats by simultaneously analyzing the activities of inhibitory and principal neurons in brain slices. Our results demonstrate that short-term in vitro ischemia permanently impairs the excitability of inhibitory neurons (IN) and synaptic transmission mediated by gamma-aminobutyric acid (GABA). However, principal neurons appear to be more exciting during the reperfusion. The vulnerability of inhibitory neurons to ischemia acquires during postnatal development. Our findings signify a major contribution of the ischemic dysfunction of inhibitory neurons to neural excitotoxicity as well as a strategy to prevent the progress of ischemic stroke by protecting inhibitory neurons.

2-Amino-5-phosphonovalerate↗
PubMed2003

Convergent responses of Barrington's nucleus neurons to pelvic visceral stimuli in the rat: a juxtacellular labelling study.

Barrington's nucleus impacts on bladder and distal colon function and relays pelvic visceral information to the forebrain. This study investigated processing of information from the bladder and the distal colon by Barrington's nucleus in the rat. The responses of individual Barrington's nucleus neurons to bladder and/or colon distention were characterized using extracellular recording and the recorded neurons were identified using juxtacellular labelling. Most neurons within Barrington's nucleus (79%) were activated by bladder distention, consistent with its role as a pontine micturition centre. Although no neurons were selectively responsive to colon distention, the majority of bladder-responsive neurons (73%) were also activated by colon distention. In a second study, Barrington's nucleus neurons were characterized with respect to their response to colon distention and their immunoreactivity for the stress-related neuropeptide corticotropin-releasing factor (CRF). Of 30 labelled neurons in the central part of Barrington's nucleus, 53% were activated by colon distention and 63% of these were CRF-ir. This is the first report demonstrating that Barrington's nucleus neurons are responsive to colon distention. The results provide evidence for convergence of information from the bladder and the colon onto individual Barrington's nucleus neurons. Taken with evidence that many Barrington's nucleus neurons are synaptically linked to the bladder and colon, the present study suggests a role for these neurons in coordinating peripheral parasympathetic and central responses to both viscera and implicate CRF as a neurotransmitter in this function. Dysfunctions in this circuit may underlie the coexistence of colon and bladder symptoms observed in functional bowel disorders.

Action Potentials↗
PubMed1995

Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options.

The presence of specific antineuronal antibodies in some patients with paraneoplastic central nervous system (CNS) disorders supports the theory that these syndromes have an autoimmune etiology. The anti-Purkinje cell antibodies (APCAs) in some patients with paraneoplastic cerebellar degeneration and ovarian or breast carcinomas stain the cytoplasm of Purkinje cells. APCAs react with several distinct neuronal protein autoantigens, including proteins featuring a "leucine zipper" sequence motif, which suggests that they function in regulating DNA transcription. Type 1 anti-neuronal nuclear antibodies (ANNA-1) associated with paraneoplastic encephalomyelitis and small-cell lung carcinoma stain the nucleus and cytoplasm of all neurons, and react with a group of 35- to 40-kd proteins in neuronal immunoblots. The protein targets of ANNA-1 belong to a family of RNA-binding proteins that probably regulate posttranscriptional processing of RNA. Type 2 anti-neuronal nuclear antibodies (ANNA-2) associated with paraneoplastic opsoclonus-ataxia and breast carcinoma also produce a panneuronal immunocytochemical staining pattern, but react with a group of higher-molecular-mass proteins (53-61 kd and 79-84 kd); these autoantigens probably also function as RNA-binding proteins. Several patients with paraneoplastic stiff-man syndrome have antibodies against a 128-kd synaptic protein. These antineuronal antibodies are highly specific (but not infallible) diagnostic markers for the presence of a neoplasm in patients who present with neurological dysfunction. The actual role of these autoantibodies in the pathogenesis of neuronal damage and clinical disease remains to be determined. Current management options for patients with CNS neurological paraneoplastic syndromes are very limited. Only a small minority of patients with paraneoplastic cerebellar degeneration or encephalomyelitis show significant neurological improvement after successful tumor treatment and/or immunosuppressive treatments, while patients with paraneoplastic opsoclonus or stiff-man syndrome have a somewhat better outlook.

Adult↗
PubMed2004

Psychopharmacology in fragile X syndrome--present and future.

In addition to cognitive disability, fragile X syndrome (FXS) is associated with behavioral problems that are often functionally limiting. There are few controlled trials to guide treatment; however, available information does suggest that medications can be quite helpful for a number of categories of behavioral disturbance in FXS. Specifically, stimulants appear to be quite useful for management of distractibility, hyperactivity, and impulsive behavior; antidepressants help with anxiety, obsessive-compulsive behaviors and mood dysregulation; and antipsychotics can reduce aggression. These medications are supportive and help minimize dysfunctional behaviors and maximize functioning. As more is learned about the neural functions of FMRP, medications in the future will be expected to target specific synaptic mechanisms dysregulated in FXS brain and thus ameliorate the cognitive deficit with resultant behavioral improvements. This article summarizes knowledge about effectiveness and approaches to management of currently available psychopharmacology for behavior in FXS and discusses early leads to future treatments for cognition.

Adrenergic alpha-Agonists↗
PubMed1995

Aluminum impairs hippocampal long-term potentiation in rats in vitro and in vivo.

Although aluminum (Al) contributes to a variety of cognitive dysfunctions and mental diseases, the underlying mechanisms of Al interactions with the nervous system are still unknown. We have studied the action of Al on synaptic transmission and long-term potentiation (LTP) by performing electrophysiological recordings both in vivo, using freely moving animals, and in vitro, using hippocampal slices. In vivo recordings of the population spikes (PSs) of dentate gyrus granule cells in response to medial perforant path stimulation were performed on both acutely and chronically (Al each day for 5 days) intraventricularly injected animals. Acute Al-infusion (calculated brain concentrations of 0.27, 0.68, and 2.7 micrograms/ml) had no influence on baseline values. Al at 0.27 microgram/ml did not alter the induction and maintenance of LTP, but 0.68 and especially 2.7 micrograms/ml Al lead to a reduction in LTP, and the potentiation declined to baseline within 2 h. In chronic animals their neuronal responsiveness was reduced and in 30% of the rats the PS was completely lost. High-frequency tetanization failed to induce LTP. In slices, field potentials were evoked stimulating Schaffer collaterals and recording pyramidal cells of the CA1 region. Bath application of 0.68 microgram/ml Al increased the baseline amplitude of the PS slightly, whereas 2.7 micrograms/ml decreased the amplitude and concentrations > 5.4 micrograms/ml blocked the PS completely. Induction of LTP in the presence of 0.68 microgram/ml Al led to a smaller increase of the PS amplitude compared to controls, but the duration of LTP was not affected. In the presence of 2.7 micrograms/ml Al LTP was further reduced and declined to baseline levels within 60 min. Given that LTP is a form of synaptic plasticity underlying some forms of learning, our data suggest that both preparations are suitable models for investigating actions of Al-induced neurotoxicity.

Aluminum↗
PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗
PubMed1998

Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation.

The E6-AP ubiquitin ligase (human/mouse gene UBE3A/Ube3a) promotes the degradation of p53 in association with papilloma E6 protein, and maternal deficiency causes human Angelman syndrome (AS). Ube3a is imprinted with silencing of the paternal allele in hippocampus and cerebellum in mice. We found that the phenotype of mice with maternal deficiency (m-/p+) for Ube3a resembles human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. Long-term potentiation (LTP) was severely impaired in m-/p+ mice despite normal baseline synaptic transmission and neuroanatomy, indicating that ubiquitination may play a role in mammalian LTP and that LTP may be abnormal in AS. The cytoplasmic abundance of p53 was increased in postmitotic neurons in m-/p+ mice and in AS, providing a potential biochemical basis for the phenotype through failure to ubiquitinate and degrade various effectors.

Acoustic Stimulation↗
PubMed2000

Corticomotoneuronal activity in ALS: changes in the peristimulus time histogram over time.

OBJECTIVE: The primary peak in the peristimulus time histogram (PSTH) reflects the initial rising phase of the excitatory post-synaptic potential (EPSP) evoked at the anterior horn cell. In ALS the primary peak is delayed in onset. increased in duration and desynchronized. abnormalities reflecting dysfunction of the corticomotoneurons. It is not known whether these abnormalities change over time in amyotrophic lateral sclerosis (ALS). METHODS: PSTHs were constructed from changes in the firing probability of single, voluntarily activated motor units subjected to subthreshold transcranial magnetic stimuli. We studied 58 motor units in 12 patients with ALS on two separate occasions (mean time interval of 10.6 +/- 1.6 months). Results were compared with 49 motor units in 11 age matched controls. RESULTS: All the parameters except the amplitude differed significantly between normals and patients. In general the primary peak in ALS was complex, desynchronized and occasionally consisted of a double peak. The abnormalities persisted or were accentuated at tile follow up visit. This was reflected by an increase in the number of excess bins, longer duration and latency and decrease of synchrony. CONCLUSIONS: Increasing desynchronization of the primary peak over time in ALS reflects dysfunction of the monosynaptic corticomotoneuronal pathway and may also reflect activation of additional slow conducting and/or polysynaptic corticomotoneuronal connections.

Adult↗
PubMed1985

Abnormal sodium transport in synaptosomes from brain of uremic rats.

The causes of central nervous system (CNS) dysfunction in uremia are not well known and are not completely reversed by dialysis. This problem was investigated in synaptosomes, which are membrane vesicles from synaptic junctions in the brain. We measured Na uptake under conditions of control, veratridine stimulation, and tetrodotoxin inhibition, in synaptosomes from normal and acutely uremic (blood urea nitrogen, 250 mg/dl) rats. In the control state, maximal Na uptake was 2.2 +/- 0.2 and 1.9 +/- 0.3 nmol/mg of protein in normal and uremic synaptosomes, respectively. With veratridine stimulation, Na uptake was increased by 1.9 and 3.6 nmol/mg of protein in normal vs. uremic rats (P less than 0.001). The increased veratridine-stimulated Na uptake observed in uremia could be due either to increased membrane permeability to Na or decrease in the Na-K ATPase pump activity. To investigate this, we studied the Na-K ATPase pump function by evaluating uptake of K (using rubidium as a tracer), uptake of Na during ATP stimulation, and inhibition of Rb and Na uptake by ouabain. In uremic rats both Rb uptake and ATP-stimulated Na uptake were significantly less than in normals (P less than 0.005). This suggests a defect in the Na-K ATPase pump. Membrane permeability for Na was then evaluated both by measuring initial Na uptake, and with addition of valinomycin. No change in Na uptake pattern was observed with valinomycin, and initial Na uptake was not significantly different in normal versus uremic synaptosomes. These data show that (a) in uremic rats veratridine-stimulated Na accumulation is significantly greater than normal; (b) the increased Na accumulation observed in uremia appears to be due to alterations in Na-K ATPase pump activity; and (c) the altered Na accumulation observed is probably not due to a uremic environment, but may be secondary to a physiologic alteration in synaptosomal function due to the uremic state. These abnormalities may affect neurotransmission and may be associated with the CNS alterations observed in uremia.

Adenosine Triphosphate↗
PubMed2006

Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia.

Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained. This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophrenia.When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D(2) receptors seems to be crucial to balancing efficacy and adverse effects - transient D(2) receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D(2) receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D(2) receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D(2) receptors. Balancing presynaptic and postsynaptic D(2) receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D(2) receptors. Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D(2) and serotonin 5-HT(2A) receptor antagonism (e.g. by olanzapine and risperidone), partial D(2) receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors. In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia.

Animals↗
PubMed2006

[Acute intoxication due to cocaine. Review of one case].

Cocaine is a drug with distribution and consumption throughout the world. Its consumption extended mainly in the decades 1980-1990. The drugs produces cardiovascular effects following chronic administration and overdose, due to their potent vasoconstrictor effect secondary to the increase of synaptic concentrations of the monamine neurotransmitter dopamine, norepinephrine, and serotonin by binding to transporter proteins and blocking reuptake. Renal insufficiency due to rhabdomyolysis, and cardiovascular dysfunction have been reported following cocaine abuse, and may be fatal. We report a patient who developed renal insufficiency due to rhabdomyolysis and a cardiovascular disorder associated with cocaine abuse. We review the disorders induced by cocaine abuse and their treatment.

Adult↗
PubMed2006

Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors.

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.

Analysis of Variance↗