Ultrastructure of cortical synapses in the brain of schizophrenics

The autopsy was performed in 225 cases of chronic schizophrenia. In 44 cases examination of the brain by light microscope revealed changes typical of Alzheimer's disease. The increased risk for the development of Alzheimer's disease in chronic schizophrenia is pointed out. In 8 schizophrenics where death occurred suddenly and unexpectedly electronmicroscopy of brain was carried out. Clusters of a great number of synaptic vesicles were found in presynaptic knobs in the brain cortex of the schizophrenics but not in the controls; the postmortal origin and/or fixation artefact origin of the clusters were excluded. The possible "immunologic dependent" clustering of synaptic vesicles is discussed. The new "modul concept" in the structure of the brain cortex is used to make the role of synapses in the mental process more clear.     

Ultrastructure of human cerebral cortical synapses: age-specific aspects

The paper deals with electron microscopic studies of the cerebral cortex in human beings aged 70-80 years. The synapses show a decrease in the number of synaptic vesicles, their impaired distribution in the presynaptic process. There are changes in the mechanisms of interaction of synaptic vesicles and a presynaptic membrane. In the latter, the vesicles loose their discreteness, some of them are replaced by a fine-granular material. The joining of the vesicles and membrane is impaired. A part of active synaptic areas is transformed to desmose-like contacts. The findings are indicative of synaptic dysfunction.     

E-cadherin is required at GABAergic synapses in cultured cortical neurons

Classical cadherins are cell adhesion molecules that are thought to contribute to the control of synapse formation, synaptic transmission, and synaptic plasticity. This is largely based on studies investigating the functions of N-cadherin at glutamatergic synapses, whereas other classical cadherins have hardly been examined at central synapses. We have now used a conditional knockout approach in cultured cortical neurons to address the role of E-cadherin mainly at inhibitory, GABAergic synapses. Cortical neurons were cultured from mouse fetuses carrying floxed E-cadherin alleles in homozygous configuration. E-cadherin knockout was induced in individual neurons by expression of an EGFP-Cre fusion protein. Immunocytochemical stainings for the vesicular GABA (VGAT) and glutamate (VGLUT1) transporters revealed a reduced density of dendritic GABAergic synapses in E-cadherin knockout neurons, whereas glutamatergic synapses were unaffected. Electrophysiological recordings of miniature and action potential-evoked, GABA_A receptor-mediated postsynaptic currents confirmed an impairment of GABAergic synapses at the functional level. In summary, our immunocytochemical and electrophysiological analysis of E-cadherin knockout neurons suggested that E-cadherin signaling importantly contributes to the regulation of GABAergic synapses in cortical neurons.     

Differential dependence of LTD on glutamate receptors in the auditory cortical synapses of cortical and thalamic inputs

Pyramidal neurons in the auditory cortex (AC) receive glutamatergic inputs from the medial geniculate body (MGB inputs) and other pyramidal neurons (pyramidal inputs). We found that the induction of long-term depression (LTD) in supragranular layers was only partially suppressed by 50 microM D-(-)-2-amino-5-phosphonovalerate (APV), an antagonist of N-methyl-D-aspartate (NMDA) receptors (NMDARs), and 500 microM (+)-alpha-methyl-4-carboxyphenylglycine (MCPG), an antagonist of metabotropic glutamate receptors (mGluRs). However, LTD was not observed in the mixture of APV and MCPG. We hypothesized that the mixed dependence of LTD on glutamate receptors could be attributed to the heterogeneity of MGB inputs and pyramidal inputs. To test this hypothesis, the angle of slicing and other recording conditions were adjusted so that postsynaptic potentials were recorded in normal slices, but not in the slices prepared from the rats with MGB lesion. In these experiments, LTD was suppressed by MCPG alone. The conditions were adjusted to minimize the contribution of MGB inputs in field potentials. In these experiments, the induction of LTD was suppressed by APV alone. Interestingly, the induction of LTD was partially suppressed by 20 microM nifedipine, a blocker of L-type Ca(2+) channels, in the slices prepared from the rats with MGB lesions, but not in normal slices. These findings suggest that the induction of LTD requires activation of mGluRs in the synapses of MGB inputs and of NMDARs in the synapses of pyramidal inputs.     

Ultrastructure of cortical synapses after failure of presynaptic activity in ischemia,

The fine structure of cerebral cortical synapses was investigated during failure of synaptic transmission produced by ischemia. Presynaptic and postsynaptic potentials evoked in the anterior sigmoid gyrus of the cat by stimulation of the nucleus ventralis lateralis and the DC potential between cortical layer IV and the white matter were recorded with micropipettes during cerebral ischemia produced by arterial hemorrhage in paralyzed, artificially ventilated animals. After failure of the spontaneous electrocorticogram and postsynaptic responses, the presynaptic volley failed with development of depolarization of intracortical fiber terminals and loss of axon terminal excitability. The gyrus was then biopsied and fixed in collidine-buffered OsO₄. An altered pattern of distribution of synaptic vesicles was observed after presynaptic afferent fiber terminal activity was abolished by 3.5 to 4.0 minutes of cerebral ischemia. Clumping of vesicles in a region away from the cynaptic cleft was seen in about 10% of synaptic endings, and there was more than a two-fold increase in the number of presynaptic profiles devoid of vesicles in ischemic cortex.     

Morphological and molecular changes in aging rat prelimbic prefrontal cortical synapses

Age-related impairments of executive functions appear to be related to reductions of the number and plasticity of dendritic spine synapses in the prefrontal cortex (PFC). Experimental evidence suggests that synaptic plasticity is mediated by the spine actin cytoskeleton, and a major pathway regulating actin-based plasticity is controlled by phosphorylated LIM kinase (pLIMK). We asked whether aging resulted in altered synaptic density, morphology, and pLIMK expression in the rat prelimbic region of the PFC. Using unbiased electron microscopy, we found an approximate 50% decrease in the density of small synapses with aging, while the density of large synapses remained unchanged. Postembedding immunogold revealed that pLIMK localized predominantly to the postsynaptic density where it was increased in aging synapses by approximately 50%. Furthermore, the age-related increase in pLIMK occurred selectively within the largest subset of prelimbic PFC synapses. Because pLIMK is known to inhibit actin filament plasticity, these data support the hypothesis that age-related increases in pLIMK may explain the stability of large synapses at the expense of their plasticity.     

The role of asymmetrical frontal cortical activity in aggression

Aggression correlates with relatively greater left than right frontal electroencephalographic activity (inverse of EEG alpha power). The present experiment extends this research by manipulating frontal asymmetry and examining its effect on aggression. Participants were assigned to increase left frontal activation or increase right frontal activation by contracting their contralateral hand. They then received insulting feedback and played a game in which they could aggress toward the person who insulted them. Right-hand contractions caused greater left than right central and frontal activation and aggression as compared to left-hand contractions. Within the right-hand contraction condition, greater relative left frontal activity was associated with greater aggression.     

Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons

Networks of GABAergic interneurons are implicated in synchronizing cortical activity at gamma frequencies (30-70 Hz). Here we demonstrate that the combined electrical and GABAergic synaptic coupling of basket cells instantaneously entrained gamma-frequency postsynaptic firing in layers 2/3 of rat somatosensory cortex. This entrainment was mediated by rapid curtailment of gap junctional coupling potentials by GABAA receptor-mediated IPSPs. Electron microscopy revealed spatial proximity of gap junctions and GABAergic synapses on somata and dendrites. Electrical coupling alone entrained postsynaptic firing with a phase lag, whereas unitary GABAergic connections were ineffective in gamma-frequency phasing. These observations demonstrate precise spatiotemporal mechanisms underlying action potential timing in oscillating interneuronal networks.     

Age-related changes in the subtypes of voltage-dependent calcium channels in rat brain cortical synapses

Age-related changes in the relative contribution of voltage-dependent calcium channel (VDCC) subtypes to depolarization-induced Ca(2+) influx and in the density of VDCC subtypes in cortical synapses were investigated using synaptosomes and their membrane preparations from brain cortices of Wistar rats. The relative contribution of VDCC subtypes to Ca(2+) influx was determined by measuring the inhibition of depolarization-induced Ca(2+) influx with four VDCC subtype-specific peptide blockers. In adult rat synaptosomes, L-, N-, P- and Q-type channels accounted for 24, 32, 27 and 12% of the total Ca(2+) influx, respectively. Brain aging significantly reduced the relative contributions of N- and P-type channels and increased the contribution of the channels resistant to the four blockers used. The densities of VDCC subtypes, determined by binding experiments using radiolabeled PN200 -110, omega-conotoxin GVIA and omega-conotoxin MVIIC, were found to be significantly decreased in aged synaptic plasma membranes. On the contrary, the dissociation constants of the blockers were not changed except for PN200-110-sensitive L-type channels. These results suggest that aging alters the relative contributions of each VDCC subtype to depolarization-induced Ca(2+) influx and decreases the number of VDCCs in rat brain cortical synapses. These changes in VDCCs may lead to age-related hypofunction of synaptic neurotransmission in brain cortices.     

NR2B-containing NMDA autoreceptors at synapses on entorhinal cortical neurons

We have previously shown that presynaptic N-methyl-D-aspartate receptors (NMDARs) can facilitate glutamate release onto principal neurons in the entorhinal cortex (EC). In the present study, we have investigated the subunit composition of these presynaptic NMDARs. We recorded miniature alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (mEPSCs), from visually identified neurons in layers II and V of the EC in vitro. In both layers, bath application of the NR2A/B subunit-selective agonist, homoquinolinic acid (HQA), resulted in a marked facilitation of mEPSC frequency. Blockade of presynaptic Ca(2+) entry through either NMDARs or voltage-gated Ca(2+) channels with Co(2+) prevented the effects of HQA, confirming that Ca(2+) entry to the terminal was required for facilitation. When the NR2B-selective antagonist, ifenprodil, was applied prior to HQA, the increase in mEPSC frequency was greatly reduced. In addition, we found that an NMDAR antagonist blocked frequency-dependent facilitation of evoked release and reduced mEPSC frequency in layer V. Thus we have demonstrated that NMDA autoreceptors in layer V of the EC bear the NR2B subunit, and that NMDARs are also present at terminals onto superficial neurons.     

Paramembranous microfibrillar structures of rat cerebral cortical synapses during sensitization by brain antigens

Department of Neurology and Neurosurgery, and Department of Histology and Embryology, Omsk Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR Yu. I. Borodin.) Translated from Byullelten' Éksperimental'noi Biologii i Meditsiny, Vol. 108, No. 11, pp. 624–626, November, 1989.     

Monoaminergic synapses in infant mouse neocortex: Comparison of cortical fields in seizure-prone and resistant mice

In a quantitative electron microscopic study, 5-hydroxydopamine was utilized to identify putative monoamine-containing synaptic boutons in the temporal and in the somatosensory cortex of 6-day-old mice. In Swiss mice, a stratiform distribution of a synapses is seen in both fields. Although the overall synaptic density is slightly lower in the temporal cortex, the relative density of small granular vesicles synapses is equivalent in both fields. In the temporal cortex of seizure-prone DBA mice, only 4% of the synapses are labeled by 5-hydroxydopamine compared with 20% in the temporal cortex of normal Swiss mice; the degree of labeling in the somatosensory cortex is comparable in both strains. Morphometric analysis of the structure of the labeled synapses suggests that the typical monoamine-containing synapse in DBA mice differs from that in Swiss mice.Assuming that 5-hydroxydopamine is a reliable marker for monoamine-containing synapses, we conclude that the temporal cortex differs in several key ways from other fields in the cortex of DBA mice and from the same region in non-seizure-prone Swiss mice.     

Defining the role of GABA in cortical development

Of the many signals in the developing nervous system, GABA (γ-aminobutyric acid) has been shown to be one of the earliest neurotransmitters present. Unlike in the adult, where this transmitter acts synaptically to inhibit neurons, during development, GABA can depolarize progenitor cells and their progeny due to their high intracellular chloride concentration. This early form of GABA signalling may provide the main excitatory drive for the immature cortical network and play a central role in regulating cortical development. Many features of GABA signalling are conserved in different species and are recapitulated during neurogenesis in the adult brain, demonstrating the importance of this versatile molecule in driving cortical formation. Here, we present recent evidence supporting the multiple functions of GABA during embryonic development and adult neurogenesis, from regulating progenitor proliferation to influencing the migration and maturation of newborn neurons.     

Representation of auditory signals in the M-cell: role of electrical synapses

The teleost Mauthner (M-) cell mediates a sound-evoked escape behavior. A major component of the auditory input is transmitted by large myelinated club endings of the posterior VIIIth nerve. Paradoxically, although nerve stimulations revealed these afferents have mixed electrical and glutamatergic synapses on the M-cell's distal lateral dendrite, paired pre- and postsynaptic recordings indicated most individual connections are chemically silent. To determine the sensory information encoded and the relative contributions of these two transmission modes, M-cell responses to acoustic stimuli in air were recorded intracellularly. Excitatory postsynaptic potentials (EPSPs) evoked by both short 100- to 900-Hz "pips" and longer-lasting amplitude- and frequency-modulated sounds were dominated by fast, repetitive EPSPs superimposed on an underlying slow depolarization. Fast EPSPs 1) have kinetics comparable to presynaptic action potentials, 2) are maximal on the distal lateral dendrite, and 3) are insensitive to GluR antagonists. They presumably are coupling potentials, and power spectral analysis indicated they constitute a high-pass signal that accurately tracks sound frequency and amplitude. The spatial profile of the slow EPSP suggests both proximal and distal dendritic sources, a result supported by predictions of a multicompartmental model and the effects of AMPAR antagonists, which preferentially reduced the proximal component. Thus a second class of afferents generates a portion of the slow EPSP that, with sound stimuli, demonstrate that the dominant mode of transmission at LMCE synapses is electrical. The slow EPSP is a dynamic, low-pass representation of stimulus strength. Accordingly, amplitude and phase information, which are segregated in other systems, are faithfully represented in the M-cell.