Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extracellular matrix is a complex network of macromolecules including glycoproteins, polysaccharides and proteoglycans. Tenascin-R and chondroitin sulfate proteoglycans are essential components of hippocampal extracellular matrix co-localised in perineuronal nets on interneurons. Mutant mice deficient in expression of tenascin-R showed a two-fold reduction of long-term potentiation induced by theta-burst stimulation of Schaffer collaterals in the stratum radiatum of the CA1 region of the hippocampus, as compared to wild-type mice. The same reduction in potentiation was observed in slices from wild-type mice pretreated for 2h with chondroitinase ABC that completely removed chondroitin sulfates from the extracellular matrix. Treatment of slices from tenascin-R deficient animals with the enzyme did not further reduce potentiation in comparison with untreated slices from these mice, showing an occlusion of effects produced by removal of tenascin-R and chondroitin sulfates. However, the level of potentiation recorded immediately after theta-burst stimulation was significantly higher in wild-type than in tenascin-R deficient mice, whereas chondroitinase ABC had no significant effect on this short-term form of plasticity. Enzymatic treatment also did not affect short-term depression evoked by low-frequency stimulation, whereas this form of synaptic plasticity was reduced in tenascin-R deficient mice. In contrast, long-term depression in CA1 was impaired by digestion of chondroitin sulfates but appeared normal in tenascin-R mutants. Our data demonstrate that tenascin-R and chondroitin sulfate proteoglycans differentially modulate several forms of synaptic plasticity, suggesting that different mechanisms are involved.
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PMID:Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. 1137 40

Mucopolysaccharidosis type IVa (MPS IVa, Morquio syndrome OMIM #253000) is a lysosomal storage disease caused by deficiency in N-acetylgalactosamine-6-sulfatase (GALNS, EC 3.1.6.4; encoded by GALNS gene at 16q24.3). Unlike other MPS disorders involving excessive heparan and dermatan sulfate, Morquio syndrome has not been associated with neurological involvement nor with intellectual impairment as this disorder of keratan sulfate has been described as a purely visceral and skeletal disorder. Neurocognitive assessment was undertaken of MPS IVa patients with age appropriate intellectual tests as well as a Child Behaviour Checklist as part of clinical follow up. Available neuroimaging studies (MRI and MR spectroscopy) were reviewed. Whilst more than half of the overall IQ scores fell in the average range, scores for 3/8 children fell below average. A number of behavioural problems were highlighted, including anxiety/depression, attention and somatic complaints. Subtle neuroimaging abnormalities were demonstrated in over half of the children. These findings present a challenge to existing assumptions about the nature of Morquio A syndrome. A hypothesis regarding the potential role of calcium signalling is explored.
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PMID:Intellectual and neurological functioning in Morquio syndrome (MPS IVa). 2223 79

Perineuronal nets (PNNs) are extracellular matrix structures surrounding cortical neuronal cell bodies and proximal dendrites and are involved in the control of brain plasticity and the closure of critical periods. Expression of the link protein Crtl1/Hapln1 in neurons has recently been identified as the key event triggering the formation of PNNs. Here we show that the genetic attenuation of PNNs in adult brain Crtl1 knock-out mice enhances long-term object recognition memory and facilitates long-term depression in the perirhinal cortex, a neural correlate of object recognition memory. Identical prolongation of memory follows localized digestion of PNNs with chondroitinase ABC, an enzyme that degrades the chondroitin sulfate proteoglycan components of PNNs. The memory-enhancing effect of chondroitinase ABC treatment attenuated over time, suggesting that the regeneration of PNNs gradually restored control plasticity levels. Our findings indicate that PNNs regulate both memory and experience-driven synaptic plasticity in adulthood.
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PMID:Depletion of perineuronal nets enhances recognition memory and long-term depression in the perirhinal cortex. 2359 63

It is currently known that in CNS the extracellular matrix is involved in synaptic stabilization and limitation of synaptic plasticity. However, it has been reported that the treatment with chondroitinase following injury allows the formation of new synapses and increased plasticity and functional recovery. So, we hypothesize that some components of extracellular matrix may modulate synaptic transmission. To test this hypothesis we evaluated the effects of chondroitin sulphate (CS) on excitatory synaptic transmission, cellular excitability, and neuronal plasticity using extracellular recordings in the CA1 area of rat hippocampal slices. CS caused a reversible depression of evoked field excitatory postsynaptic potentials in a concentration-dependent manner. CS also reduced the population spike amplitude evoked after orthodromic stimulation but not when the population spikes were antidromically evoked; in this last case a potentiation was observed. CS also enhanced paired-pulse facilitation and long-term potentiation. Our study provides evidence that CS, a major component of the brain perineuronal net and extracellular matrix, has a function beyond the structural one, namely, the modulation of synaptic transmission and neuronal plasticity in the hippocampus.
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PMID:Chondroitin Sulfate Induces Depression of Synaptic Transmission and Modulation of Neuronal Plasticity in Rat Hippocampal Slices. 2607 99

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS.
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PMID:Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats. 2926 33

Perineuronal nets (PNNs), composed mainly of chondroitin sulfate proteoglycans, are the extracellular matrix that surrounds cell bodies, proximal dendrites, and axon initial segments of adult CNS neurons. PNNs are known to regulate neuronal plasticity, although their physiological roles in cerebellar functions have yet to be elucidated. Here, we investigated the contribution of PNNs to GABAergic transmission from cerebellar Purkinje cells (PCs) to large glutamatergic neurons in the deep cerebellar nuclei (DCN) in male mice by recording IPSCs from cerebellar slices, in which PNNs were depleted with chondroitinase ABC (ChABC). We found that PNN depletion increased the amplitude of evoked IPSCs and enhanced the paired-pulse depression. ChABC treatment also facilitated spontaneous IPSCs and increased the miniature IPSC frequency without changing not only the amplitude but also the density of PC terminals, suggesting that PNN depletion enhances presynaptic GABA release. We also demonstrated that the enhanced GABAergic transmission facilitated rebound firing in large glutamatergic DCN neurons, which is expected to result in the efficient induction of synaptic plasticity at synapses onto DCN neurons. Furthermore, we tested whether PNN depletion affects cerebellar motor learning. Mice having received the enzyme into the interpositus nuclei, which are responsible for delay eyeblink conditioning, exhibited the conditioned response at a significantly higher rate than control mice. Therefore, our results suggest that PNNs of the DCN suppress GABAergic transmission between PCs and large glutamatergic DCN neurons and restrict synaptic plasticity associated with motor learning in the adult cerebellum.SIGNIFICANCE STATEMENT Perineuronal nets (PNNs) are one of the extracellular matrices of adult CNS neurons and implicated in regulating various brain functions. Here we found that enzymatic PNN depletion in the mouse deep cerebellar nuclei (DCN) reduced the paired-pulse ratio of IPSCs and increased the miniature IPSC frequency without changing the amplitude, suggesting that PNN depletion enhances GABA release from the presynaptic Purkinje cell (PC) terminals. Mice having received the enzyme in the interpositus nuclei exhibited a higher conditioned response rate in delay eyeblink conditioning than control mice. These results suggest that PNNs regulate presynaptic functions of PC terminals in the DCN and functional plasticity of synapses on DCN neurons, which influences the flexibility of adult cerebellar functions.
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PMID:Perineuronal Nets in the Deep Cerebellar Nuclei Regulate GABAergic Transmission and Delay Eyeblink Conditioning. 2985 84

Long-term depression (LTD) of synaptic efficacy is widely regarded as a cellular basis of learning and memory. The magnitude of hippocampal CA1 LTD induced by low-frequency stimulation (LFS) declines with age, but the mechanisms involved remain poorly understood. Perineuronal nets (PNNs) are specialized extracellular matrix structures that function in dampening synaptic plasticity during postnatal development, suggesting that PNN formation may restrict LTD induction in the adult hippocampus. Here, we show that PNNs tightly enwrap a subpopulation of parvalbumin (PV) interneurons in the hippocampal CA1 region and enzymatic removal of PNNs with the chondroitinase ABC alters the excitatory/inhibitory synaptic balance toward more excitation and restores the ability of LFS to induce an N-methyl-D-aspartate receptor-dependent LTD at Schaffer collateral-CA1 synapses in slices from male adult mice. Early interference with depolarizing GABA with Na+-K+-2Cl- cotransporter inhibitor bumetanide impairs the maturation of PNNs and enhances LTD induction. These results provide novel insights into a previously unrecognized role for PNNs around PV interneurons in restricting long-term synaptic plasticity at excitatory synapses on hippocampal CA1 neurons in adulthood.
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PMID:Perineuronal Nets Restrict the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region. 3082 67