Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficits in parvalbumin containing interneurons are a consistent observation in animal models and schizophrenia patients. These neurons are surrounded by chondroitin sulfate proteoglycans, forming perineuronal nets, thought to support the high firing frequencies observed in these neurons. A loss of perineuronal nets has been observed post mortem in human schizophrenia patients, however, whether this contributes to the symptoms of schizophrenia is not known. Here we directly examine the effects of chondroitinase ABC degradation of ventral hippocampal (vHipp) perineuronal nets, and demonstrate that this results in an enhanced hippocampal activity and significant increase in dopamine neuron population activity. In addition, chondroitinase-treated rats display an augmented locomotor response to amphetamine, consistent with the enhanced response to psychomotor stimulants observed in schizophrenia patients. Taken together, these data demonstrate that a loss of vHipp perineuronal nets is sufficient, in and of itself, to induce aberrant hippocampal and dopamine system function consistent with that observed in rodent models and schizophrenia patients.
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PMID:A loss of hippocampal perineuronal nets produces deficits in dopamine system function: relevance to the positive symptoms of schizophrenia. 2332 12

Extracellular matrix (ECM) molecules, their receptors at the cell surface, and cell adhesion molecules (CAMs) involved in cell-cell or cell-ECM interactions are implicated in processes related to major diseases of the central nervous system including Alzheimer's disease (AD), epilepsy, schizophrenia, addiction, multiple sclerosis, Parkinson's disease, and cancer. There are multiple strategies for targeting the ECM molecules and their metabolizing enzymes and receptors with antibodies, peptides, glycosaminoglycans, and other natural and synthetic compounds. ECM-targeting treatments include chondroitinase ABC, heparin/heparan sulfate-mimicking oligosaccharides, ECM cross-linking antibodies, and drugs stimulating expression of ECM molecules. The amount or activity of ECM-degrading enzymes like matrix metalloproteinases can be modulated indirectly via the regulation of endogenous inhibitors like TIMPs and RECK or at the transcriptional and translational levels using, e.g., histone deacetylase inhibitors, synthetic inhibitors like Periostat, microRNA-interfering drugs like AC1MMYR2, and natural compounds like flavonoids, epigallocatechin-3-gallate, anacardic acid, and erythropoietin. Among drugs targeting the major ECM receptors, integrins, are the anticancer peptide cilengitide and anti-integrin antibodies, which have a potential for treatment of stroke, multiple sclerosis, and AD. The latter can be also potentially treated with modulators of CAMs, such as peptide mimetics derived from L1-CAM and NCAM1.
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PMID:Targeting of ECM molecules and their metabolizing enzymes and receptors for the treatment of CNS diseases. 2541 Mar 65

Perineuronal nets (PNNs) are highly organized components of the extracellular matrix that surround a subset of mature neurons in the CNS. These structures play a critical role in regulating neuronal plasticity, particularly during neurodevelopment. Consistent with this role, their presence is associated with functional and structural stability of the neurons they ensheath. A loss of PNNs in the prefrontal cortex (PFC) has been suggested to contribute to cognitive impairment in disorders such as schizophrenia. However, the direct consequences of PNN loss in medial PFC (mPFC) on cognition has not been demonstrated. Here, we examined behavior after disruption of PNNs in mPFC of Long-Evans rats following injection of the enzyme chondroitinase ABC (ChABC). Our data show that ChABC-treated animals were impaired on tests of object oddity perception. Performance in the cross-modal object recognition (CMOR) task was not significantly different for ChABC-treated rats, although ChABC-treated rats were not able to perform above chance levels whereas control rats were. ChABC-treated animals were not significantly different from controls on tests of prepulse inhibition (PPI), set-shifting (SS), reversal learning, or tactile and visual object recognition memory. Posthumous immunohistochemistry confirmed significantly reduced PNNs in mPFC due to ChABC treatment. Moreover, PNN density in the mPFC predicted performance on the oddity task, where higher PNN density was associated with better performance. These findings suggest that PNN loss within the mPFC impairs some aspects of object oddity perception and recognition and that PNNs contribute to cognitive function in young adulthood.
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PMID:Impaired Cognitive Function after Perineuronal Net Degradation in the Medial Prefrontal Cortex. 3062 57