Tau-associated filamentous aggregates are neuropathological hallmarks of Alzheimer’s disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), whereas α-synuclein-positive Lewy bodies are features of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Factors underlying the genesis and functional impact of these aggregates remain poorly understood. Protein kinase M zeta (PKMζ), the catalytic fragment of PKCζ, plays a key role in the maintenance of long-term potentiation, a widely studied model of memory and synaptic plasticity (Ling et al. Nat Neurosci 5:295, 2002). We have demonstrated an association of PKMζ and atypical PKCs (ι and ζ) with neurofibrillary tangles and Hirano bodies in AD (Crary et al. Soc Neurosci Abs, 2002). In the present study, we investigated the relationship of atypical PKCs and PKMζ to abnormal inclusions in PiD (n=2); PSP (n=3); CBD (n=3); and DLB with AD (n=3). Immunohistochemical study was performed on autopsy brain t...

Recent evidence suggests that endogenous cannabinoids in the CNS inhibit neuronal activity and neurotransmitter release. These effects are mediated by Gi/o coupled CB1 receptors, which are abundantly expressed in cerebellum, hippocampus, cortex and basal ganglia. Additional evidence suggests that CB1 receptor signaling is negatively modulated in a use-dependent fashion. The novel regulators of G protein signaling (RGS) proteins have potent GTPase activating effects at Gi/o subunits and thus could subserve negative feedback of CB1R signaling. We are using several lines of investigation to test this hypothesis. Six hr after an acute injection of THC, or 24 hr after a 15 d regimen of daily THC injections, mice were killed and processed for in situ hybridization to RGS4 mRNA in sections of prefrontal cortex, striatum, and cerebellum. RGS4 mRNA levels were increased in entorhinal cortex and hippocampus with a trend towards increased expression in striatum, but not in thalamus, 6 hr after an acute injection of T...

Delta9-tetrahydrocannabinol and anandamide (ANA) are the vegetal and the animal marijuana, respectively. They promote overeating and affect sexual behavior. Oleamide (OLE) is an endogenous sleep-inducing lipid, with several cannabinoid-like properties. OLE effects on feeding and sexual behavior were evaluated and compared with those induced by ANA. Experiment 1. Food satiated male Wistar rats received intraperitoneal (i.p.) injections of OLE or ANA (0.5, 1.0, 2.0 and 4.0 mg/kg) or vehicle. Food intake was measured at 1, 2, and 3 hours following injection. Experiment 2. Male sexual behavior was evaluated in Wistar rats after the i.p. administration of OLE, ANA (doses as above) or vehicle. Experimental males were exposed to estrogenous + progesterone-induced receptive females, 15 min after the injection. Both food intake and sexual behavior tests were carried out during the first half of the dark phase. Results showed that all doses of OLE and ANA induced significant overeating, with only one exception, ANA ...

Alcoholism causes neurological disorders such as memory loss and cognitive disfunction. Binge drinking, the repeated consumption of high levels of alcohol over a several day period, is a widespread form of alcoholism in society today. One of the mechanisms leading to alcohol-induced neurotoxicity appears to be oxidative stress. This study demonstrates that administration of antioxidants such as alpha tocopherol (Vitamin E), butylhydroxytoluene (BHT), and cannabidiol (CBD) significantly reduce neurotoxicity in the hippocampal-entorhinal complex of rats in a binge-type model of alcoholism. The diuretic furosemide has also been shown to prevent neurotoxicity in this model. The proposed mechanism of action was linked to the reduction of edema. Using the binge-model we compared furosemide with two similar compounds, bumetanide and L-644,711. L-644,711 has previously been shown to be protective in an edema-based model of brain injury. However, in the present study, furosemide was found to be neuroprotective whil...

Cannabis sativa alters sensory perception and exhibits potential medicinal benefits. In mammals, cannabinoids activate two canonical receptors, CB1/CB2, as well additional receptors/ion channels whose overall contributions to cannabinoid signaling have yet to be fully assessed. In Caenorhabditis elegans , the endogenous cannabinoid receptor agonist, 2-arachidonoylglycerol (2-AG) activates a CB1 ortholog, NPR-19, to modulate behavior ([Oakes et al., 2017][1]). In addition, 2-AG stimulates the NPR-19 independent release of both serotonin (5-HT) and dopamine (DA) from subsets of monoaminergic neurons to modulate locomotory behaviors through a complex monoaminergic signaling pathway involving multiple serotonin and dopamine receptors. 2-AG also inhibits locomotion in remodeled monoamine receptor mutant animals designed to measure the acute release of either 5-HT or DA, confirming the direct effects of 2-AG on monoamine release. 2-AG-dependent locomotory inhibition requires the expression of transient receptor ...

Several studies suggest that cannabinoids induce biological effects through specific receptors distinct from the cloned CB1 and CB2 receptors. Of all the cannabinoid agonists currently available, the prototypical aminoalkylindole compound WIN55212-2 is ...

The charged multivesicular body protein 2B gene (CHMP2B) was recently identified as the gene responsible for frontotemporal lobar degeneration (FTLD) linked to the pericentromeric region of chromosome 3. To date, linkage to this region was unique to a l...

CaV2.1 channels conduct P/Q-type Ca2+ currents that are modulated by calmodulin (CaM) and the structurally related Ca2+-binding protein 1 (CaBP1). Visinin-like protein-2 (VILIP-2) is a CaM-related Ca2+-binding protein expressed in the neocortex and hippocampus. Coexpression of CaV2.1 and VILIP-2 in tsA-201 cells resulted in Ca2+ channel modulation distinct from CaM and CaBP1. CaV2.1 channels with β2a subunits undergo Ca2+-dependent facilitation and inactivation attributable to association of endogenous Ca2+/CaM. VILIP-2 coexpression does not alter facilitation measured in paired-pulse experiments but slows the rate of inactivation to that seen without Ca2+/CaM binding and reduces inactivation of Ca2+ currents during trains of repetitive depolarizations. CaV2.1 channels with β1b subunits have rapid voltage-dependent inactivation, and VILIP-2 has no effect on the rate of inactivation or facilitation of the Ca2+ current. In contrast, when Ba2+ replaces Ca2+ as the charge carrier, VILIP-2 slows inactivation. T...

Thyroid receptor-interacting protein 6 (Trip6), a multifunctional protein belonging to the zyxin family of LIM proteins, is involved in various physiological and pathological processes, including cell migration and tumorigenesis. However, the role of Trip6 in neurons remains unknown. Here, we show that Trip6 is expressed in mouse hippocampal neurons and promotes dendritic morphogenesis. Through interaction with the glutamate receptor-interacting protein 1 (GRIP1) and myosin VI, Trip6 is crucial for the total dendritic length and the number of primary dendrites in cultured hippocampal neurons. Trip6 depletion reduces F-actin content and impairs dendritic morphology, and this phenocopies GRIP1 or myosin VI knockdown. Furthermore, phosphorylation of GRIP1956T by AKT1 inhibits the interaction between GRIP1 and myosin VI, but facilitates GRIP1 binding to 14-3-3 protein, which is required for regulating F-actin organization and dendritic morphogenesis. Thus, the Trip6–GRIP1–myosin VI interaction and its regulati...

The Battle of the LTDs in the Cerebellum Wolfgang Mittmann and Michael Häusser (see pages [5559–5570][1]) Purkinje cells provide the sole output of cerebellar cortex, thus serving as the final common pathway for cerebellar synaptic integration and plasticity. The cellular plasticity