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PubMed2003

Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development.

Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.

Adolescent↗
PubMed2005

Control of synaptic strength and timing by the release-site Ca2+ signal.

Transmitter release is triggered by highly localized, transient increases in the presynaptic Ca(2+) concentration ([Ca(2+)]). Rapidly decaying [Ca(2+)] elevations were generated using Ca(2+) uncaging techniques, and [Ca(2+)] was measured with a low-affinity Ca(2+) indicator in a giant presynaptic terminal, the calyx of Held, in rat brain slices. The rise time and amplitude of evoked excitatory postsynaptic currents (EPSCs) depended on the half-width of the fluorescence transient, which was predicted by a five-binding site model of a Ca(2+) sensor having relatively high affinity (K(d) approximately 13 microM). Very fast [Ca(2+)] transients (half-width <0.5 ms) evoked EPSCs similar to those elicited by a single action potential (AP) in the same synapse. Triggering release with dual [Ca(2+)] transients of variable amplitudes demonstrated the supralinear transfer function of the sensor. The sensitivity of release to the time course of the [Ca(2+)] transient may contribute to mechanisms by which the presynaptic AP waveform controls synaptic strength.

Acetates↗
PubMed1995

Arachidonic acid, but not sodium nitroprusside, stimulates presynaptic protein kinase C and phosphorylation of GAP-43 in rat hippocampal slices and synaptosomes.

Activation of protein kinase C (PKC) and phosphorylation of its presynaptic substrate, the 43-kDa growth-associated protein GAP-43, may contribute to the maintenance of hippocampal long-term potentiation (LTP) by enhancing the probability of neurotransmitter release and/or modifying synaptic morphology. Induction of LTP in rat hippocampal slices by high-frequency stimulation of Schaffer collateral-CA1 synapses significantly increased the PKC-dependent phosphorylation of GAP-43, as assessed by quantitative immunoblotting with a monoclonal antibody that recognizes an epitope that is specifically phosphorylated by PKC. The stimulatory effect of high-frequency stimulation on levels of immunoreactive phosphorylated GAP-43 was not observed when 4-amino-5-phosphonovalerate (50 microM), an N-methyl-D-aspartate (NMDA) receptor antagonist, was bath-applied during the high-frequency stimulus. This observation supports the hypothesis that a retrograde messenger is produced postsynaptically following NMDA receptor activation and diffuses to the presynaptic terminal to activate PKC. Two retrograde messenger candidates--arachidonic acid and nitric oxide (sodium nitroprusside was used to generate nitric oxide)--were examined for their effects in hippocampal slices on PKC redistribution from cytosol to membrane as an indirect measure of enzyme activation and PKC-specific GAP-43 phosphorylation. Bath application of arachidonic acid, but not sodium nitroprusside, at concentrations that produce synaptic potentiation (100 microM and 1 mM, respectively) significantly increased translocation of PKC immunoreactivity from cytosol to membrane as well as levels of immunoreactive, phosphorylated GAP-43. The stimulatory effect of arachidonic acid on GAP-43 phosphorylation was also observed in hippocampal synaptosomes. These results indicate that arachidonic acid may contribute to LTP maintenance by activation of presynaptic PKC and phosphorylation of GAP-43 substrate. The data also suggest that nitric oxide does not activate this signal transduction system and, by inference, activates a distinct biochemical pathway.

Animals↗
PubMed2005

Overexpression of drebrin A in immature neurons induces the accumulation of F-actin and PSD-95 into dendritic filopodia, and the formation of large abnormal protrusions.

Drebrin A is a neuron-specific F-actin binding protein, and plays a pivotal role in the spine formation. In this study, we expressed drebrin A tagged with green fluorescent protein (GFP-DA) in hippocampal neurons at 7-9 days in vitro when presynaptic terminals are not fully maturated. GFP-DA was accumulated in dendritic protrusions and formed large abnormal structures. Since these structures were similar to filopodia in terms of lack of MAP2 immunostaining, we named them "megapodia" meaning large dendritic filopodia. F-actin and PSD-95 were also accumulated in megapodia, and their amounts were significantly correlated with that of GFP-DA. However, the expression of GFP-DA did not result in the promotion of the morphological change from filopodia into spines. These results demonstrate that drebrin A accumulates spine-resident proteins via protein-protein interaction in filopodia, and suggest that the spine formation requires the concurrence of the increase of drebrin-A expression and the functional presynaptic contact.

Actins↗
PubMed2000

The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors.

Nefiracetam, a pyrrolidone derivative developed as an anti-dementia drug, persistently potentiated currents through neuronal nicotinic acetylcholine (ACh) receptors (alpha7, alpha4beta2) expressed in Xenopus oocytes, and the potentiation was blocked by either the selective protein kinase C (PKC) inhibitors, GF109203X and staurosporine, or co-expressed active PKC inhibitor peptide. In primary cultures of rat hippocampal neurons, nefiracetam increased the rate of nicotine-sensitive miniature excitatory postsynaptic currents, without affecting the amplitude, and the increase was inhibited by GF109203X. In addition, the drug caused a marked increase in the glutamate release from electrically stimulated guinea pig hippocampal slices, and the effect was abolished by the nicotinic ACh receptor antagonists, alpha-bungarotoxin and mecamylamine. Nefiracetam induced a long-lasting facilitation of synaptic transmission in both the CA1 area and the dentate gyrus of rat hippocampal slices, and the facilitation was inhibited by alpha-bungarotoxin and mecamylamine. Such facilitatory action was still found in the hippocampus with selective cholinergic denervation. The results of the present study, thus, suggest that nefiracetam enhances activity of nicotinic ACh receptors by interacting with a PKC pathway, thereby increasing glutamate release from presynaptic terminals, and then leading to a sustained facilitation of hippocampal neurotransmission. This may represent a cellular mechanism underlying the cognition-enhancing action of nefiracetam. The results also provide the possibility that nefiracetam could be developed as a promising therapeutic drug for senile dementia or Alzheimer's disease.

Animals↗
PubMed1999

Modulation by K+ channels of action potential-evoked intracellular Ca2+ concentration rises in rat cerebellar basket cell axons.

1. Action potential-evoked [Ca2+]i rises in basket cell axons of rat cerebellar slices were studied using two-photon laser scanning microscopy and whole-cell recording, to identify the K+ channels controlling the shape of the axonal action potential. 2. Whole-cell recordings of Purkinje cell IPSCs were used to screen K+ channel subtypes which could contribute to axonal repolarization. alpha-Dendrotoxin, 4-aminopyridine, charybdotoxin and tetraethylammonium chloride increased IPSC rate and/or amplitude, whereas iberiotoxin and apamin failed to affect the IPSCs. 3. The effects of those K+ channel blockers that enhanced transmitter release on the [Ca2+]i rises elicited in basket cell axons by action potentials fell into three groups: 4-aminopyridine strongly increased action potential-evoked [Ca2+]i; tetraethylammonium and charybdotoxin were ineffective alone but augmented the effects of 4-aminopyridine; alpha-dendrotoxin had no effect. 4. We conclude that cerebellar basket cells contain at least three pharmacologically distinct K+ channels, which regulate transmitter release through different mechanisms. 4-Aminopyridine-sensitive, alpha-dendrotoxin-insensitive K+ channels are mainly responsible for repolarization in basket cell presynaptic terminals. K+ channels blocked by charybdotoxin and tetraethylammonium have a minor role in repolarization. alpha-Dendrotoxin-sensitive channels are not involved in shaping the axonal action potential waveform. The two last types of channels must therefore exert control of synaptic activity through a pathway unrelated to axonal action potential broadening.

4-Aminopyridine↗
PubMed2000

Structural and functional alterations of neuromuscular junctions in NCAM-deficient mice.

The role of neural cell adhesion molecule (NCAM) in the development and maturation of the neuromuscular junction (NMJ) was explored by characterizing structurally and functionally NMJs from postnatal day 11 (P11) to P30 +/+, +/-, and -/- NCAM null mutant mice. Differences in NCAM levels resulted in alterations in the size and shape of NMJs, with -/- NMJs being smaller. Additionally both the withdrawal of polyneuronal innervation and the selective accumulation of synaptic vesicle protein in the presynaptic terminal were delayed. These observations suggest that the bidirectional signaling responsible for these events is impaired at -/- NMJs. Functionally, miniature end plate potential size, end plate potential size, and quantal content did not differ from that of wild type under either normal or low release conditions. However at normal release conditions, -/- NMJs, unlike +/+ NMJs, lacked paired-pulse facilitation. The most striking abnormality was the inability of NCAM null junctions to maintain transmitter output with repetitive stimuli. Combined electrophysiological and FM1-43-labeling studies suggest that NCAM null junctions are unable either to dock or to mobilize a sufficient number of vesicles at high but physiological rates of transmitter release. Taken together our observations show that many aspects of transmission are normal and, thus, that many presynaptic and postsynaptic molecules have assembled properly in the absence of NCAM. However, the fact that NCAM was required for specific aspects of transmission, including paired-pulse facilitation and reliable transmission with repetitive stimuli, suggests that NCAM either is directly involved in these processes or is required for the proper organization and/or function of other molecules underlying these processes.

Animals↗
PubMed2006

Stable expression of the vesicular GABA transporter following photothrombotic infarct in rat brain.

Before exocytotic release of the inhibitory neurotransmitter GABA, this amino acid has to be stored in synaptic vesicles. Accumulation of GABA in vesicles is achieved by a specific membrane-integrated transporter termed vesicular GABA transporter. This vesicular protein is mainly located at presynaptic terminals of GABAergic interneurons. In the present study we investigated the effects of focal ischemia on the expression of the vesicular GABA transporter. Vesicular GABA transporter mRNA and protein expression was examined after photothrombosis in different cortical and hippocampal brain regions of Wistar rats. In situ hybridization and quantitative real-time RT-PCR were performed to analyze vesicular GABA transporter mRNA. Both vesicular GABA transporter mRNA-stained perikarya and mRNA expression levels remained unaffected. Vesicular GABA transporter protein-containing synaptic terminals and somata were visualized by immunohistochemistry. The pattern of vesicular GABA transporter immunoreactivity as well as the protein expression level revealed by semiquantitative image analysis and by Western blot remained stable after stroke. The steady expression of vesicular GABA transporter mRNA and protein after photothrombosis indicates that the exocytotic release mechanism of GABA is not affected by ischemia.

Animals↗
PubMed2002

Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2.

Hypocretin 2 (orexin B) is a hypothalamic neuropeptide thought to be involved in regulating energy homeostasis, autonomic function, arousal, and sensory processing. Neural circuits in the caudal nucleus tractus solitarius (NTS) integrate viscerosensory inputs, and are therefore implicated in aspects of all these functions. We tested the hypothesis that hypocretin 2 modulates fast synaptic activity in caudal NTS areas that are generally associated with visceral sensation from cardiorespiratory and gastrointestinal systems. Hypocretin 2-immunoreactive fibers were observed throughout the caudal NTS. In whole-cell recordings from neurons in acute slices, hypocretin 2 depolarized 48% and hyperpolarized 10% of caudal NTS neurons, effects that were not observed when Cs(+) was used as the primary cation carrier. Hypocretin 2 also increased the amplitude of tractus solitarius-evoked excitatory postsynaptic currents (EPSCs) in 36% of neurons and significantly enhanced the frequency of spontaneous EPSCs in most (59%) neurons. Spontaneous inhibitory postsynaptic currents (IPSCs) were relatively unaffected by the peptide. The increase in EPSC frequency persisted in the presence of tetrodotoxin, suggesting a role for the peptide in regulating glutamate release in the NTS by acting at presynaptic terminals. These data suggest that hypocretin 2 modulates excitatory, but not inhibitory, synapses in caudal NTS neurons, including viscerosensory inputs. The selective nature of the effect supports the hypothesis that hypocretin 2 plays a role in modulating autonomic sensory signaling in the NTS.

Action Potentials↗
PubMed2003

Palmitoyl protein thioesterase 1 is targeted to the axons in neurons.

Palmitoyl protein thioesterase 1 (PPT1) is a depalmitoylating enzyme whose deficiency leads to infantile neuronal ceroid lipofuscinosis. The disease is characterized by early loss of vision and massive neuronal death. Although PPT1 is expressed in many tissues, a deficiency of PPT1 damages neurons only in the cerebral and cerebellar cortexes and retina; other cell types remain relatively unaffected. We previously demonstrated that PPT1 is present in the synaptosomes and synaptic vesicles of neurons. To understand the crucial role of PPT1 for neuronal cells, we further investigated the expression and targeting of PPT1 in retinal, hippocampal, and cortical neurons during their maturation in culture. We found that PPT1 activity increases by neuronal maturation and is highest in retinal neuron cultures. In retinal neurons the expression of PPT1 precedes that of the synaptic vesicle protein 2 and synaptophysin, indicating a significant role for PPT1 in the early development of neuronal cells. We also found by quantitative confocal immunofluorescence microscopy that PPT1 is targeted preferably to axons in mature neurons, as indicated by its colocalization with the axonal marker microtubule-associated protein 1. In axons PPT1 is targeted specifically to axonal varicosities and presynaptic terminals, as indicated by its significant colocalization with growth-associated protein 43 and synaptophysin. Axonal localization of PPT1 was confirmed by double labeling with synaptophysin and postembedding immunoelectron microscopy. The polarized axonal targeting of PPT1 may well indicate a role for PPT1 in the exocytotic pathway of neurons.

Animals↗
PubMed2005

Colocalization of vesicular glutamate transporters in the rat superior olivary complex.

Vesicular glutamate transporters (VGLUTs) are responsible for the accumulation of the excitatory neurotransmitter glutamate into synaptic vesicles. It is currently controversial whether the two isoforms found in glutamatergic neurons, VGLUT1 and VGLUT2, are present at the same synapse or have entirely complementary patterns of distribution. Using fluorescent immunohistochemistry, this study examines the colocalization of these two transporters in the rat superior olivary complex (SOC) between postnatal day (P) 5 and 29. The medial and lateral superior olives (MSO; LSO) stain for both VGLUT1 and VGLUT2 at all ages studied, with VGLUT1 levels doubling over this developmental period and VGLUT2 levels remaining unchanged. The ventral nucleus of the trapezoid body (VNTB) strongly labels only for VGLUT2, despite the fact that glutamatergic synapses are present that are formed from collaterals of axons that go on to form synapses containing both VGLUT1 and VGLUT2. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are surrounded by the calyx of Held presynaptic terminal, which is large enough to allow examination of VGLUT localization within a synapse. Throughout its postnatal developmental period a single calyx synapse contains both VGLUT1 and VGLUT2. Whereas VGLUT1 levels are greatly up-regulated from P5 to P29, VGLUT2 levels remain high. As the abundance of VGLUT determines the quantal size, this up-regulation will increase excitatory postsynaptic currents (EPSCs) and have influences on synaptic physiology.

Aging↗
PubMed2004

Association of potassium channel Kv3.4 subunits with pre- and post-synaptic structures in brainstem and spinal cord.

Voltage-gated K+ channels (Kv) are divided into eight subfamilies (Kv1-8) and play a major role in determining the excitability of neurones. Members of the Kv3 subfamily are highly abundant in the CNS, with each Kv3 gene (Kv3.1-Kv3.4) exhibiting a unique pattern of expression, although single neurones can express more than one subtype. Of the Kv3 subunits relatively little is known of the Kv3.4 subunit distribution in the nervous system, particularly in the brainstem and spinal cord of the rat. We performed immunohistochemistry to determine both the cellular and sub-cellular distribution of the Kv3.4 subunit in these areas. Kv3.4 subunit immunoreactivity (Kv3.4-IR) was widespread, with dense, punctate staining in many regions including the intermediolateral cell column (IML) and the dorsal vagal nucleus (DVN), nucleus ambiguus (NA) and nucleus tractus solitarius (NTS). In the ventral horn a presynaptic location was confirmed by co-localization of Kv3.4-IR with the synaptic vesicle protein, SV2 and also with the glutamate vesicle markers vesicular glutamate transporter (VGluT) 1, VGluT2 or the glycine transporter GlyT2, suggesting a role for the channel in both excitatory and inhibitory neurotransmission. Electron microscopy confirmed a presynaptic terminal location of Kv3.4-IR in the VH, IML, DVN, NA and NTS. Interestingly however, patches of Kv3.4-IR were also revealed postsynaptically in dendritic and somatic structures throughout these areas. This staining was striking due to its localization at synaptic junctions at terminals with morphological features consistent with excitatory functions, suggesting an association with the postsynaptic density. Therefore the pre and postsynaptic localization of Kv3.4-IR suggests a role both in the control of transmitter release and in regulating neuronal excitability.

Amino Acid Transport Systems, Neutral↗
PubMed1999

Target-specific factors regulate the formation of glutamatergic transmitter release sites in cultured neocortical neurons.

Synapse formation in the mammalian CNS is thought to involve specific target recognition processes between presynaptic and postsynaptic neurons leading to the establishment of defined neuronal circuits. To study the role of target neuron-specific factors in synaptogenesis, we used cocultures of presynaptic explants and dissociated target neurons from rat neocortex, which enabled us to selectively vary the postsynaptic target neurons. Cocultures containing target neurons that were obtained early during development [embryonic day 16 (E16)] were compared to cocultures containing target neurons that were obtained at a later embryonic stage (E19). Postsynaptic currents (PSCs) were evoked in target neurons by maximal extracellular stimulation in the presynaptic explant. The mean amplitudes of AMPA and NMDA receptor-mediated PSCs were sixfold reduced in E16 target neurons, whereas the mean amplitudes of GABA(A) receptor-mediated PSCs did not differ between E16 and E19 target neurons. This reduction was in part caused by an apparently twofold reduction in mean quantal amplitude, as shown by recording AMPA receptor-mediated miniature PSCs. In addition, a reduced number of glutamatergic release sites in E16 target neurons was revealed by synapsin I immunostaining of dendritic presynaptic terminals. No differences in mean release probability were observed between E16 and E19 target neurons. Thus, the formation of glutamatergic transmitter release sites was strongly influenced by target neuron-specific factors. The formation of functional GABAergic synapses, however, was independent of the type of target neurons, suggesting specific retrograde signaling during the establishment of glutamatergic synapses.

Animals↗
PubMed2003

Distribution and ultrastructural localization of torsinA immunoreactivity in the human brain.

We have examined the distribution and ultrastructural localization of torsinA, the protein product of the TOR1A gene, in the normal adult human and Macaque brain. TorsinA immunoreactivity was visualized using a monoclonal antibody raised against a fusion protein encoding exon 4 of human torsinA. Western blot analysis of brain homogenates revealed a major species of about 39 kDa, consistent with the predicted size of glycosylated torsinA protein. By light microscopy, torsinA like-immunoreactivity was enriched in gray matter in all brain regions examined. Immunoreactivity was concentrated in the neuropil and immunopositive cell bodies were not observed. Structures particularly enriched in torsinA like-immunoreactivity included the cerebral cortex, the caudate-putamen, globus pallidus, the hippocampal formation, the thalamus, the substantia nigra and molecular cell layer of the cerebellar cortex. Cell bodies of pigmented dopamine neurons in the substantia nigra pars compacta were immunonegative. Biochemical fractionation of the human striata revealed a concentration of torsinA immunoreactivity in particulate fractions. Ultrastructural studies of the human and Macaque striata further revealed an association of torsinA immunostaining with small vesicles within axons and presynaptic terminals forming symmetric synapses. These ultrastructural studies are consistent with a pre-synaptic localization of torsinA protein in the adult striatum and are consistent with a role of torsinA in modulating striatal signaling, although the widespread localization of the protein suggests it probably also participates in signaling in other regions.

Animals↗
PubMed2005

Differential regulation of GABA(A) receptor and gephyrin postsynaptic clustering in immature hippocampal neuronal cultures.

Gephyrin is a postsynaptic scaffolding protein involved in clustering of glycine- and GABA(A) receptors at inhibitory synapses. The role of gephyrin in GABAergic synapses, the nature of its interactions with GABA(A) receptors, and the mechanisms of targeting to GABAergic synapses are largely unknown. To gain further insights into these questions, the formation of GABA(A) receptor and gephyrin clusters and their distribution relative to presynaptic terminals were investigated in immature cultures of embryonic hippocampal neurons using triple immunofluorescence staining. GABA(A) receptor clusters, labeled for the alpha2 subunit, formed independently of gephyrin clusters, and were distributed on neurites at constant densities, either extrasynaptically or, to a lesser extent, postsynaptically, apposed to synapsin-I-positive axon terminals. In contrast, gephyrin clusters were always associated with GABA(A) receptors and were preferentially localized postsynaptically. Their density increased linearly with the extent of innervation, which developed rapidly during the first week in vitro. These results suggested that GABA(A) receptor clustering is mediated by cell-autonomous mechanisms independent of synapse formation. Their association with gephyrin is dynamically regulated and may contribute to stabilization at postsynaptic sites. Labeling for vesicular glutamate transporters revealed that most synapses in these immature cultures were presumably glutamatergic, implying that postsynaptic GABA(A) receptor and gephyrin clusters initially were located in "mismatched" synapses. However, clusters appropriately localized in GABAergic synapses were distinctly larger and more intensely stained. Altogether, these results demonstrate that the targeting of GABA(A) receptor and gephyrin clusters to GABAergic synapses occurs secondarily and is regulated by presynaptic factors that are not essential for clustering.

Animals↗
PubMed2006

VGLUTs: 'exciting' times for glutamatergic research?

Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate is first synthesized in the cytoplasm of presynaptic terminals before being loaded into synaptic vesicles, which fuse with the plasma membrane, releasing their contents, in response to neuronal activity. The important process of synaptic vesicle loading is mediated by a transport protein, collectively known as vesicular glutamate transporter (VGLUT). Controlling the activity of these transporters could potentially modulate the efficacy of glutamatergic neurotransmission. In recent years, three isoforms of mammalian VGLUTs have been cloned and molecularly characterized in detail. Probing these three VGLUTs has been proven to be the most reliable way of visualizing sites of glutamate release in the mammalian CNS. Immunohistochemical studies on VGLUTs suggest that glutamatergic neurons are categorized into subgroups depending on which VGLUT isoform they contain. Recent studies on VGLUT1-deficient mice have led various models to be postulated concerning the possible roles of VGLUTs in synaptic physiology, such as presynaptic regulation of quantal size and activity-dependent short-term plasticity.

Animals↗
PubMed2001

Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders.

It is currently a widely accepted opinion that adaptive, plastic changes in the molecular and cellular components of neuronal signaling systems correlate with the effects on mood and cognition observed after long-term treatment with antidepressant drugs. Protein phosphorylation represents a key step for most signaling systems, and it is involved in the regulation of virtually all cellular functions. Two serine/threonine kinases, Ca2+ /calmodulin-dependent protein kinase II and cyclic AMP-dependent protein kinase, have been shown to be activated in the brain following antidepressant treatment. The changes in kinase activity are mirrored by changes in the phosphorylation of selected protein substrates in subcellular compartments (presynaptic terminals and microtubules), which, in turn, may contribute to the modulation of synaptic transmission observed with antidepressants. The molecular consequences of protein kinase activation may account for some of the alterations in neural function induced by antidepressants, and may suggest novel possible strategies of pharmacological intervention.

Animals↗
PubMed2000

Synaptic alterations in the vestibulocerebellar system in Alzheimer's disease--a Golgi and electron microscope study.

Alzheimer's disease is one of the main causes of cognitive impairment in the presenium and senium. Despite increased efforts in investigations of the aetiological background of the disease, most of the pathogenetic mechanisms remain unclear. From the morphological point of view, neurofibrillary degeneration and neuritic plaques, the main hallmarks of Alzheimer's disease, are mostly seen in the hippocampus and the cortex of the cerebral hemispheres. In contrast, the cerebellum and brain stem demonstrate minimal aggregates of neurofibrillary tangles. In addition, the neuronal population is better preserved in the cerebellum in contrast to the cortex of the brain hemispheres. In this study we attempted to detect alterations to the synapses in the vestibulocerebellar system, which is better preserved than the other structures in the central nervous system, even in the advanced stages of Alzheimer's disease. The morphological analysis is based on examination of 10 brains via electron microscopy and silver impregnation in the nodule, flocculus and vestibular nuclei. Morphological analysis revealed a limited number of neuritic plaques and minimal neurofibrillary tangles. However, synaptic alterations of the mossy fibres, granule cell dendrites, parallel fibres and Purkinje cell dendritic spines were extensively seen in Alzheimer's brains, in contrast to normal controls. In the granule layer, granule and Golgi cells were considerably decreased in number. The synapses between the mossy fibres and the granule cell dendrites were also decreased. Some of the synapses contained a limited number of polymorphous synaptic vesicles, numerous atypical mitochondria and dense bodies. Most synaptic alterations were in the mossy fibres' presynaptic terminals. The number of synaptic contacts between the mossy fibre terminals and the dendrites of the granule and Golgi cells was dramatically decreased. In the vestibular nuclei, substantial loss of synapses among the local neuronal circuits was also observed. Morphological alterations of the Golgi apparatus were seen in several neurons of the medial and lateral vestibular nuclei. In conclusion, these observations obviously plead in favour of a synaptic pathology among the primary pathogenetic processes in Alzheimer's.

Aged↗