Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional maturation of visual cortex is linked with dynamic changes in synaptic expression of GABAergic mechanisms. These include setting the excitation-inhibition balance required for experience-dependent plasticity, as well as, intracortical inhibition underlying development and aging of receptive field properties. Animal studies have shown that there is developmental regulation of GABAergic mechanisms in visual cortex. In this study, we show for the first time how these mechanisms develop in the human visual cortex across the lifespan. We used Western blot analysis of postmortem tissue from human primary visual cortex (n = 30, range: 20 days to 80 years) to quantify expression of eight pre- and post-synaptic GABAergic markers. We quantified the inhibitory modulating cannabinoid receptor (CB1), GABA vesicular transporter (VGAT), GABA synthesizing enzymes (GAD65/GAD67), GABA(A) receptor anchoring protein (Gephyrin), and GABA(A) receptor subunits (GABA(A)alpha1, GABA(A)alpha2, GABA(A)alpha3). We found a complex pattern of different developmental trajectories, many of which were prolonged and continued well into the teen, young adult, and even older adult years. These included a monotonic increase or decrease (GABA(A)alpha1, GABA(A)alpha2), a biphasic increase then decrease (GAD65, Gephyrin), or multiple increases and decreases (VGAT, CB1) across the lifespan. Comparing the balances between the pre- and post-synaptic markers we found three main transition stages (early childhood, early teen years, aging) when there were rapid switches in the composition of the GABAergic signaling system, indicating that functioning of the GABAergic system must change as the visual cortex develops and ages. Furthermore, these results provide key information for translating therapies developed in animal models into effective treatments for amblyopia in humans.
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PMID:Developmental changes in GABAergic mechanisms in human visual cortex across the lifespan. 2059 50

Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of the disease and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse.
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PMID:The role of cannabinoid 1 receptor expressing interneurons in behavior. 2423 60