Postsynaptic Damage Research Articles

Microglia proliferation underlies synaptic dysfunction in the prefrontal cortex: implications for the pathogenesis of HIV-1-associated neurocognitive and affective alterations.

Microglia, which are productively infected by HIV-1, are critical for brain development and maturation, as well as synaptic plasticity. The pathophysiology of HIV-infected microglia and their role in the pathogenesis of HIV-1-associated neurocognitive and affective alterations, however, remains understudied. Three complementary aims were undertaken to critically address this knowledge gap. First, the expression of HIV-1 mRNA in the dorsolateral prefrontal cortex of postmortem HIV-1 seropositive individuals with HAND was investigated. Utilization of immunostaining and/orRNAscope multiplex fluorescent assays revealed prominent HIV-1 mRNA in microglia of postmortem HIV-1 seropositive individuals with HAND. Second, measures of microglia proliferation and neuronal damage were evaluated in chimeric HIV (EcoHIV) rats. Eight weeks after EcoHIV inoculation, enhanced microglial proliferation was observed in the medial prefrontal cortex (mPFC) of EcoHIV rats, evidenced by an increased number of cells co-localized with both Iba1 + and Ki67 + relative to control animals. Neuronal damage in EcoHIV infected rats was evidenced by pronounced decreases in both synaptophysin and postsynaptic density protein 95 (PSD-95), markers of presynaptic and postsynaptic damage, respectively. Third, regression analyses were conducted to evaluate whether microglia proliferation mechanistically underlies neuronal damage in EcoHIV and control animals. Indeed, microglia proliferation accounted for 42-68.6% of the variance in synaptic dysfunction. Collectively, microglia proliferation induced by chronic HIV-1 viral protein exposure may underlie the profound synaptodendritic alterations in HIV-1. Understanding how microglia are involved in the pathogenesis of HAND and HIV-1-associated affective disorders affords a key target for the development of novel therapeutics.

Electrocochleography in Auditory Neuropathy Related to Mutations in the OTOF or OPA1 Gene.

Auditory Neuropathy (AN) is characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in alterations of auditory perceptions. Mutations in several genes have been associated to the most forms of AN. Underlying mechanisms include both pre-synaptic and post-synaptic damage involving inner hair cell (IHC) depolarization, neurotransmitter release, spike initiation in auditory nerve terminals, loss of auditory fibers and impaired conduction. In contrast, outer hair cell (OHC) activities (otoacoustic emissions [OAEs] and cochlear microphonic [CM]) are normal. Disordered synchrony of auditory nerve activity has been suggested as the basis of both the alterations of auditory brainstem responses (ABRs) and reduction of speech perception. We will review how electrocochleography (ECochG) recordings provide detailed information to help objectively define the sites of auditory neural dysfunction and their effect on receptor summating potential (SP) and neural compound action potential (CAP), the latter reflecting disorders of ribbon synapses and auditory nerve fibers.

Postsynaptic damage and microglial activation in AD patients could be linked CXCR4/CXCL12 expression levels

Alzheimer's disease (AD) is one of the most common forms of dementia with still unknown pathogenesis. Several cytokines and chemokines are involved in the pathogenesis of AD. Among the chemokines, the CXCR4/CXCL12 complex has been shown to play an important role in the pathogenetic development of AD.We investigated the expression levels of CXCR4 / CXCL12 in fifteen brain regions of healthy non-demented subjects (NDHC) (2139 sample) and AD patients (1170 sample) stratified according to sex and age. Furthermore, we correlated their expressions with the Neurogranin (NRGN) and CHI3L1 levels, two inflamm-aging markers.We highlighted that CXCR4 gene expression levels were age-correlated in the brain of NDHC subjects and that AD nullified this correlation. A similar trend, but diametrically opposite was observed for CXCL12. Its expression was decreased during the aging in both sexes, and in the brains of AD patients, it underwent an inversion of the trend, only and exclusively in females. Brains of AD patients expressed high CXCR4 and CHI3L1, and low CXCL12 and Neurogranin levels compared to NDHC subjects. Both CXCR4 and CXCL12 correlated significantly with CHI3L1 and Neurogranin expression levels, regardless of disease. Furthermore, we showed a selective modulation of CXCL12 and CXCR4 only in specific brain regions.Taken together our results demonstrate that CXCL12 and CXCR4 are linked to Neurogranin and CHI3L1 expression levels and the relationship between postsynaptic damage and microglial activation in AD could be shown using all these genes. Further confirmations are needed to demonstrate the close link between these genes.

SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response.

Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.

Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity.

The goal of this study was to identify the intrinsic links that explain the effect of a Western diet (WD) on cognitive dysfunction. Specific pathogen-free, wild-type mice were fed either a control diet (CD) or a high-fat, high-sucrose WD after weaning and were euthanized at 10 mo of age to study the pathways that affect cognitive health. The results showed that long-term WD intake reduced hippocampal synaptic plasticity and the level of brain-derived neurotrophic factor mRNA in the brain and isolated microglia. A WD also activated ERK1/2 and reduced postsynaptic density-95 in the brain, suggesting postsynaptic damage. Moreover, WD-fed mice had increased inflammatory signaling in the brain, ileum, liver, adipose tissue, and spleen, which was accompanied by microglia activation. In the brain, as well as in the digestive tract, a WD reduced signaling regulated by retinoic acid and bile acids (BAs), whose receptors form heterodimers to control metabolism and inflammation. Furthermore, a WD intake caused dysbiosis and dysregulated BA synthesis with reduced endogenous ligands for BA receptors, i.e., farnesoid X receptor and G-protein-coupled bile acid receptor in the liver and brain. Together, dysregulated BA synthesis and dysbiosis were accompanied by systemic inflammation, microglial activation, and reduced neuroplasticity induced by WD.-Jena, P. K., Sheng, L., Di Lucente, J., Jin, L.-W., Maezawa, I., Wan, Y.-J. Y. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity.

Expression of A2V-mutated Aβ in Caenorhabditis elegans results in oligomer formation and toxicity

Although Alzheimer's disease (AD) is usually sporadic, in a small proportion of cases it is familial and can be linked to mutations in β-amyloid precursor protein (APP). Unlike the other genetic defects, the mutation [alanine-673→valine-673] (A673V) causes the disease only in the homozygous condition with enhanced amyloid β (Aβ) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of Aβ is affected in vivo by this mutation and whether this correlates with its toxic effects. No animal models over-expressing the A673V–APP gene or alanine-2-valine (A2V) mutated human Aβ protein are currently available. Using the invertebrate Caenorhabditis elegans, we generated the first transgenic animal model to express the human Aβ1–40 wild-type (WT) in neurons or possess the A2V mutation (Aβ1–40A2V). Insertion of an Aβ-mutated gene into this nematode reproduced the homozygous state of the human pathology. Functional and biochemical characteristics found in the A2V strain were compared to those of transgenic C. elegans expressing Aβ1–40WT. The expression of both WT and A2V Aβ1–40 specifically reduced the nematode's lifespan, causing behavioral defects and neurotransmission impairment which were worse in A2V worms. Mutant animals were more resistant than WT to paralysis induced by the cholinergic agonist levamisole, indicating that the locomotor defect was specifically linked to postsynaptic dysfunctions. The toxicity caused by the mutated protein was associated with a high propensity to form oligomeric assemblies which accumulate in the neurons, suggesting this to be the central event involved in the postsynaptic damage and early onset of the disease in homozygous human A673V carriers.

Wnt-5aoccludes Aβ oligomer-induced depression of glutamatergic transmission in hippocampal neurons

BackgroundSoluble amyloid-β (Aβ;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation.ResultsWe report here that the Wnt signaling activation prevents the synaptic damage triggered by Aβ oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Aβ oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Aβ oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Aβ oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Aβ oligomers inversely modulate postsynaptic components.ConclusionThese results indicate that post-synaptic damage induced by Aβ oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation.

Longitudinal in Vivo Positron Emission Tomography Imaging of Infected and Activated Brain Macrophages in a Macaque Model of Human Immunodeficiency Virus Encephalitis Correlates with Central and Peripheral Markers of Encephalitis and Areas of Synaptic Degeneration

Human immunodeficiency virus encephalitis is characterized by infiltration of the brain with infected and activated macrophages; however, it is not known why disease occurs after variable lengths of infection in 25% of immunosuppressed acquired immune deficiency syndrome patients. We determined in vivo correlates (in peripheral blood and the central nervous system) for the development and progression of lentiviral encephalitis by longitudinally following infected and activated macrophages in the brain using positron emission tomography (PET). Using human postmortem brain tissues from both lentivirus-infected encephalitic patients and cell culture systems, we showed that the PET ligand [(3)H](R)-PK11195 bound specifically to virus-infected and activated macrophages. We longitudinally imaged infected and activated brain macrophages in a cohort of macaques infected with simian immunodeficiency virus using [(11)C](R)-PK11195. [(11)C](R)-PK11195 retention in vivo in the brain correlated with viral burden in the brain and cerebrospinal fluid, and with regions of both presynaptic and postsynaptic damage. Finally, longitudinal changes in [(11)C](R)-PK11195 retention in the brain in vivo correlated with changes in circulating monocytes as well as in both natural killer and memory CD4(+) T cells in the periphery. Our results suggest that development and progression of simian immunodeficiency virus encephalitis in vivo correlates with changes in specific cell subtypes in the periphery. A combination of PET imaging and the assessment of these peripheral immune parameters may facilitate longitudinal assessment of lentiviral encephalitis in living patients as well as evaluation of therapeutic efficacies.

Parkinson's disease, chronic hydrocarbon exposure and striatal neuronal damage: A 1-H MRS study

Several patients with Parkinson’ s disease (PD) reveal an history of chronic exposure to hydrocarbon-solvents. Chronic exposure to hydrocarbon-solvents has been proposed as a risk factor for more severe forms of PD with earlier onset of symptoms and reduced response to dopaminergic therapy. A direct correlation between disease severity and exposure degree has been previously shown. Seven exposed PD patients (two with low degree exposure and five with high degree exposure), 10 unexposed PD patients matched for sex, age and Hoehn and Yahr scale (=3 in the “on” phase), and 10 unexposed PD patients matched for sex, age and l-dopa daily intake instead of disease severity (Hoehn and Yahr scale = 3.5 in the “on” phase) were studied. Twenty normal subjects without previous exposure to hydrocarbon-solvents and matched for age and sex with HPD patients were studied for comparison. The purpose of the study was to assess neuronal degeneration in the striatum of exposed vs unexposed PD patients. The authors investigated whether neuronal damage/loss was detectable in the lentiform nucleus measuring N-acetylaspartate (NAA) levels by 1-H MRS. Multiple single voxel MRS water-suppressed spectra were obtained also from the white matter and the occipital lobe. NAA was normal in the lentiform nucleus of patients with low exposure as well as in patients with no exposure whereas it was decreased in PD patients with high degree exposure. White matter and occipital lobe NAA content was normal both in exposed and unexposed PD patients. Clinical expression is more severe in PD patients with previous high degree solvent exposure because of the associated post-synaptic damage of the nigro-striatal pathway.

Acetylcholine receptors loss and postsynaptic damage in MuSK antibody–positive myasthenia gravis

Muscle-specific tyrosine kinase (MuSK) antibodies are found in some patients with "seronegative" myasthenia gravis (MG), but how they cause myasthenic symptoms is not clear. We visualized acetylcholine receptors (AChRs) and complement component 3 (C3) in muscle biopsies from 10 Japanese MG patients with MuSK antibodies, compared with 42 with AChR antibodies. The AChR density was not significantly decreased in MuSK antibody (Ab)-positive end-plates compared with AChR antibody-positive end-plates, and C3 was detected in only two of eight MuSK Ab-positive patients. MuSK antibodies do not appear to cause substantial AChR loss, complement deposition, or morphological damage. Effects on MuSK function need to be explored.

Induction of striatal pre- and postsynaptic damage by methamphetamine requires the dopamine receptors

Methamphetamine (METH) is a psychostimulant that induces excessive release of dopamine (DA) in the striatum. In this study we have assessed the role of DA D1 and D2 receptors (D1R and D2R) on striatal METH-induced apoptosis and depletion of DA-terminal markers. Male mice were given one i.p. injection of METH (30 mg/kg). Apoptosis was assessed at 24 h, and DA-terminal marker depletion 3 days, after METH. A single toxic dose of METH induced apoptosis in approximately 10-13% of striatal neurons. This was completely prevented by pretreatment (30 min before METH) with either the D1R antagonist SCH-23390 (0.1 mg/kg) or the D2R antagonist raclopride (1 mg/kg). The same dose of METH induced depletion of DA transporter sites up to 61, 56, 71, and 69% in dorsal-medial, ventral-medial, dorsal-lateral, and ventral-lateral striatum, respectively, relative to vehicle-injected controls. Similarly, METH induced depletion of TH protein levels up to 80, 72, 87, and 90% in those respective quadrants. METH induced the expression of glial fibrillary acidic protein throughout the striatum. All these neurochemical changes were significantly attenuated by pretreatment with SCH-23390 (0.1 mg/kg) or raclopride (1 mg/kg). However, pretreatment with either raclopride or SCH-23390 did not prevent METH-induced hyperthermia in mice. These data demonstrate that the induction by METH of both striatal apoptosis and DA-terminal damage requires the activity of the postsynaptic DA receptors in the mouse brain. Moreover, since blockade of either receptor subtype protected from METH, the activity of both DA receptor subtypes is required for the induction of toxicity by METH in the striatum.

Histological evidence supporting a role for the striatal neurokinin-1 receptor in methamphetamine-induced neurotoxicity in the mouse brain

Several studies have documented the effect of methamphetamine (METH) on the toxicity of the dopamine (DA) terminals of the striatum but only a few studies have assessed the damaging effects of METH on striatal neurons postsynaptic to the nigrostriatal DA terminals. In the present study, we employed histological methods to study the effect of METH on DA terminals and striatal neurons. We also assessed the role of the striatal neurokinin-1 (NK-1) receptor on pre- and post-synaptic METH-induced damage. Male mice were treated with METH (10 mg/kg) four times at 2-h intervals and were sacrificed 3 days after the treatment. A number of animals received the non-peptide NK-1 receptor antagonist WIN-51,708 (10 mg/kg) 30 min before the first and fourth injections of METH. Immunocytochemical staining for tyrosine hydroxylase (TH) showed significant deficits throughout all aspects of the caudate-putamen in animals exposed to METH. Pretreatment with WIN-51,708 prevented the METH-induced loss of TH immunostaining. Sections from a separate set of mice were stained with Fluoro-Jade B (FJB), a fluorochrome that binds specifically to degenerating fibers and cell bodies of neurons. Treatment with METH shows Fluoro-Jade B positive cell bodies in the striatum and pretreatment with WIN-51,708 abolished Fluoro-Jade B staining. Moreover, double labeling with Fluoro-Jade B and glial fibrillary acidic protein (GFAP) shows reactive astrocytosis in the area adjacent to the Fluoro-Jade B-positive cells but no Fluoro-Jade B staining of the astrocytes. This observation suggests that the degenerating cells must be striatal neurons and not astrocytes. The data demonstrate that METH induces pre- and post-synaptic damage in the striatum and the damage can be prevented with pharmacological blockade of the NK-1 receptor. These findings represent a new direction in the study of the mechanism of toxicity to METH and could be useful in the treatment of some neurological disorders.

Macrophages Relate Presynaptic and Postsynaptic Damage in Simian Immunodeficiency Virus Encephalitis

Neurodegeneration observed in lentiviral-associated encephalitis has been linked to viral-infected and -activated central nervous system macrophages. We hypothesized that lentivirus, macrophages, or both lentivirus and macrophages within distinct microenvironments mediate synaptic damage. Using the simian immunodeficiency virus (SIV)-infected macaque model, we assessed the relationship between virus, macrophages, and neurological damage in multiple brain regions using laser confocal microscopy. In SIV-infected macaques with SIV encephalitis (SIVE), brain tissue concentrations of SIV RNA were 5 orders of magnitude greater than that observed in nonencephalitic animals. In SIVE, staining for postsynaptic protein microtubule-associated protein-2 was significantly decreased in the caudate, hippocampus, and frontal cortical gray matter compared to nonencephalitic controls, whereas staining for presynaptic protein synaptophysin was decreased in SIV-infected macaques with and without encephalitis. These data suggest that presynaptic damage occurs independent of pathological changes associated with SIVE, whereas postsynaptic damage is more tightly linked to regional presence of both activated and infected macrophages.

Electrophysiologic changes in lumbar spinal cord after cervical cord injury.

Spontaneous activity on the EMG examination is traditionally ascribed to disease of the lower motor neuron when present in muscles well below the level of para- or quadriplegia despite the absence of any detectable peripheral nerve injury. It is uncertain whether it reflects transient paralysis of transmission (related to clinical spinal shock) or irreversible postsynaptic damage. We performed serial EMG studies of lower extremities and paraspinal muscles on eight young, previously healthy adults, commencing 2 to 9 weeks after acute cervical cord injury. All had stimulated single-fiber EMG (SFEMG) studies at 6-month intervals to determine whether irreversible postsynaptic damage of the anterior horn cell had occurred. MRI and nerve conduction excluded patients with evidence of distal cord injury or peripheral neuropathy. All patients had spontaneous activity in all muscles tested, persisting after spinal shock had resolved. Jitter was present on SFEMG in three of eight patients 6 months after injury. Four of five patients retested 12 months after injury had abnormal jitter, including three who initially had normal SFEMG studies. We conclude that there is electrophysiologic evidence of trans-synaptic distal cord dysfunction following acute spinal cord injury. SFEMG studies suggest that anterior horn cell dropout occurs during the 1st year after injury.

A Sequential Study of the Peripheral Nervous System Involvement in Experimental Chagas' Disease

To search for the sequential compromise of the spinal cord, nerves, and skeletal muscle in mice chronically infected with Trypanosoma cruzi, animals were subjected to electromyographic investigation, end-plate recordings, and histological studies at 7, 15, 37, 60, 90, 120, 180, 270, and 360 days postinfection. Electromyographic studies showed signs of motor unit remodeling as early as 15 days postinfection, when diminished duration and amplitude of motor unit potentials pointing to a primary muscle involvement were found. Thereafter, certain features of denervation, reinnervation, and primary muscle involvement were often found to coexist. Low miniature end-plate potentials with normal frequency and acetylcholine quantum content were found in end-plate recordings made at the phrenic-diaphragm in vitro. Double end-plate potentials were observed in most of the tested muscle fibers from day 90 postinfection. All these features suggest post-synaptic damage of the end-plate and the presence of reinnervation after day 90 postinfection. Histological studies disclosed inflammatory infiltrates consisting of lymphocytes and macrophages, with vasculitis as the main lesion in the hamstring muscles; intracellular parasites were seen in 25% of the cases. Neuropathic features, as expressed by type fiber grouping and grouped muscle fiber atrophy, were found. On nerve examination epineural, perineural, and endoneural vasculitis were seen. Digestion chambers and myelin ovoids (axonal degeneration) were observed. In teased fiber preparations, segmental internodal and paranodal demyelination and remyelination were found. The lumbar inflammatory spinal cord failed to show grey or white matter infiltrates. However, spinal roots and dorsal root ganglia were densely affected by inflammatory cells.

Oxidative damage in the guinea pig hippocampal slice

Free radicals and active oxygen compounds are implicated in brain ischemia and head trauma. Previous studies have shown that free radicals, generated by radiation and through the Fenton reaction, produce both synaptic and postsynaptic damage in the hippocampal brain slice. 1,2,3 To evaluate the contribution of oxidation to the observed damage the actions of the oxidants, chloramine-T and N-chlorosuccinimide (NCS), were studied on electrophysiological responses in the hippocampal slice isolated from the brains of guinea pigs. Electrical stimulation of afferents to neurons of the CAI region of hippocampus evoked a population postsynaptic potential (population PSP) in the dendritic layer and a population spike in the cell body layer. Chloramine-T (25–500 μM) and NCS (750–4000 μM) decreased the population spike in a dose-dependent manner ( ED 50 ⋍ 125 μ M and 1100 μM, respectively). Input/output curves revealed that both the population spike and the population PSP were significantly reduced with both oxidants; but, the ability of the population PSP to produce a population spike was not impaired. These studies suggest that oxidation reactions can account for the synaptic component of the damage produced by free radicals but can not account for the postsynaptic effects.

Mechanisms of ischemic brain damage.

This article provides a brief review of recent developments regarding the pathophysiology of ischemic brain damage, and offers hypotheses explaining the pathogenesis of selective neuronal vulnerability and of tissue infarction, respectively. It is suggested that selective neuronal vulnerability, observed after brief periods of ischemia and after hypoglycemic coma, qualifies as an excitotoxic lesion, which causes postsynaptic damage to neurons innervated by excitatory amino acids by enhancing calcium influx. However, ischemic damage often involves glial and vascular cells as well, and causes infarction. It is hypothesized that this type of brain damage is related to acidosis and that enhanced acidosis is detrimental because it accelerates delocalization of protein-bound iron, with an ensuing free-radical damage to membrane lipids and proteins.

Ionizing Radiation Alters Neuronal Excitability in Hippocampal Slices of the Guinea Pig

To investigate the effects of ionizing radiation on an isolated neuronal network without complicating systemic factors, slices of hippocampus from the guinea pig were isolated and studied in vitro. Slices were irradiated with a 60Co source and compared to paired, sham-irradiated controls. Electrophysiological activity in the CA 1 population of pyramidal cells was evoked by stimulation of the stratum radiatum. Analysis of the somatic and dendritic responses suggested sites of radiation damage. Orthodromically evoked activity was significantly decreased in slices receiving greater than 75 Gy gamma radiation. The effects were dose and dose-rate dependent. At 20 Gy/min, doses of 50 Gy and greater produced synaptic impairment while doses of 75 Gy and greater also produced postsynaptic damage (i.e., the ability of the synaptic response to generate an action potential). A lower dose rate, 5 Gy/min, reduced the sensitivity of synaptic damage to radiation exposure; synaptic impairment required a dose of 100 Gy or greater at the lower dose rate. In contrast, postsynaptic damage was not sensitive to dose rate. This study demonstrates that ionizing radiation can directly affect the integrated functional activity of neurons.

Peroxide alters neuronal excitability in the CA1 region of guinea-pig hippocampus in vitro

Effects of peroxidative damage on neuronal excitability were investigated with electro-physiological techniques in CA1 pyramidal cells of the hippocampal slice preparation. Hydrogen peroxide alone or combined with ferrous ions (peroxide/iron) is likely to produce hydroxyl free radicals through the Fenton reaction. Intracellularly recorded excitatory postsynaptic potentials and inhibitory postsynaptic potentials were significantly reduced by exposure to peroxide, while responses to iontophoretically applied GABA and glutamate were unaffected. These results suggest that peroxide has presynaptic actions. Peroxide and peroxide/iron also increased frequency adaptation; after exposure, neurons fired fewer action potentials at a lower frequency in response to the same depolarizing current step. A voltage clamp analysis revealed that the potassium currents were unaffected by peroxide/iron. Calcium current was not obviously altered by exposure to peroxide. Sodium spike threshold was also unaffected. Calcium spike threshold was significantly increased by peroxide. This action of peroxide may underlie its presynaptic actions. It is concluded that peroxide produces both presynaptic and postsynaptic damage. This damage is likely to result from the production of free radicals which have been postulated to underlie a number of pathological states.