Is the Effect of Serotonin on Neurogenesis Concentration Dependent?August Agyemang, Barbara Beltz and Paula Chaves da SilvaWellesley College, 106 Central Street, Wellesley, Massachusetts, 02481vagyeman@wellesley.eduAbstractAdult neurogenesis, a process ...

Transcriptional Regulation of Acetylcholinesterase Shelley Camp, Antonella De Jaco, Limin Zhang, Michael Marquez, Brian De La Torre, and Palmer Taylor (see pages [2459–2470][1]) Acetylcholinesterase (AChE) expression increases dramatically as myoblasts and neuroblasts differentiate

The human MAPT, or tau, locus is divided into two haplotypes, H1 and H2, with H1 being associated with the sporadic neurodegenerative dementias, Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). In PSP and CBD it has been shown there is an increase in expression of transcript and protein incorporating exon 10, encoding an extra microtubule binding repeat, in brain regions affected by neurodegeneration. We therefore propose that polymorphisms within the MAPT H1 haplotype sequence are responsible for subtle, higher levels of exon 10+, or 4R, tau transcript expression from H1 chromosomes, leading, over time, to a greater susceptibility to neurodegenerative disease. To investigate this hypothesis, we examined allele-specific expression in heterozygous cell lines and post-mortem brain tissues. The expression assays use haplotype-defining SNPs to perform allele-specific primer extensions, followed by quantitation of the extension products on the Sequenom MALDI-TOF platform. We first ident...

The psychoactive component of marijuana, Δ-9-tetrahydrocannabinol, is analogous to the brain’s own endogenous lipids called endocannabinoids. Endocannabinoids are retrograde messengers at inhibitory synapses of the CA1 region of the hippocampus. By modulating GABA release at these synapses, endocannabinoids likely play a significant role in the primary functions of the hippocampus, namely in learning and memory. Endocannabinoids can be released in a Ca2+-dependent or -independent manner and bind to the endocannabinoid receptor, CB1, on presynaptic terminals and suppress the release of GABA. This is seen as a reduction of inhibitory postsynaptic current (IPSC) on the pyramidal cell. Ca2+-dependent endocannabinoid release causes “depolarization induced suppression of inhibition,” (DSI). Activation of the Group I metabotropic receptors (mGluR), which include the two subtypes mGluR1 and mGluR5, on pyramidal cells suppresses IPSC amplitude and enhances DSI. It is not clear what contribution each receptor makes ...

Endocannabinoids and Δ9-tetrahydrocannabinol, the major psychoactive compound in marijuana, bind to and activate the cannabinoid CB1 receptor. The CB1 receptor is the most abundant G-protein coupled receptor in brain, with high levels of expression in the hippocampus, striatum, cortex and reward centers of the basal ganglia. Activation of CB1 leads to decreased excitatory and inhibitory neurotransmitter release in several brain regions through activation of GIRK channels and inhibition of voltage-gated calcium channels. In vivo responses to cannabinoid receptor agonists have been generally measured using four behavioral assays; hypothermia, spontaneous activity, analgesia and catalepsy. Despite its abundance in the brain, little is known about mechanisms that modulate CB1 receptor signaling. Here we show that PKCε, a member of the novel subclass of PKC isozymes, mediates behavioral sensitivity to both endogenous and exogenous cannabinoids. In these studies, PKCε null mice showed enhanced analgesia and hypo...

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 8–12% of children globally. Hyperactivity-related behaviors, as well as inattention and impulsivity, are regarded as the nuclear symptoms of ADHD. At present, its etiologies and risk factors are unknown. Previous research linked TARP γ-8 deficiency to ADHD-like behaviors in mice, including hyperactivity, impulsivity, and memory deficits. Aniracetam, a nootropic drug, enhances cognition by modulating cholinergic activity and glutamate receptors, offering neuroprotective effects. This study examined TARP γ-8 knockout (KO) mice at 4 and 8 weeks, assessing behaviors through locomotor activity, cliff avoidance, novel object recognition, and contextual fear conditioning tests. TARP γ-8 KO mice exhibited hyperactivity, reduced recognition memory, and impaired short-term memory and long-term memory. Aniracetam administration improved these behavioral deficits, suggesting its potential as a therapeutic agent for ADHD. The ...

Excitotoxicity associated with the N-methyl-D-aspartate (NMDA) receptor is thought to be involved in several neurodegenerative disorders. The cannabinoids exert many of their actions in brain through the CB1 cannabinoid receptor. We have examined the effect of cannabinoids on NMDA-induced excitotoxicity in the rat AF5 CNS cell line (Truckenmiller et al., Exp. Neurol., 2002). AF5 cells were briefly exposed to NMDA (5 mM -10 mM) and returned to culture medium for 22 hr. NMDA produced a dose-dependent decrease in viability as determined by mitochondrial tetrazolium formazan (MTT). Immunocytochemistry demonstrated that AF5 cells express NMDA receptor 1, and expression was increased following exposure to NMDA. Single-stranded DNA and caspase-3 staining indicated that NMDA induced apoptotic cell death. Western blotting showed that AF5 cells express the CB1 receptor. The synthetic cannabinoid agonist WIN55212-2 and delta-9 tetrahydrocannabinol (THC) were examined for protection against NMDA-induced excitoxicity. ...

The endocannabinoid anandamide [ N -arachidonoylethanolamine (AEA)] is thought to function as an endogenous protective factor of the brain against acute neuronal damage. However, this has never been tested in an in vivo model of acute brain injury. Here, we show in a longitudinal pharmacological magnetic resonance imaging study that exogenously administered AEA dose-dependently reduced neuronal damage in neonatal rats injected intracerebrally with the Na+/K+-ATPase inhibitor ouabain. At 15 min after injury, AEA (10 mg/kg) administered 30 min before ouabain injection reduced the volume of cytotoxic edema by 43 ± 15% in a manner insensitive to the cannabinoid CB1receptor antagonist SR141716A. At 7 d after ouabain treatment, 64 ± 24% less neuronal damage was observed in AEA-treated (10 mg/kg) rats compared with control animals. Coadministration of SR141716A prevented the neuroprotective actions of AEA at this end point. In addition, (1) no increase in AEA and 2-arachidonoylglycerol levels was detected at 2, 8...

The active constituents of cannabis act through the G-protein coupled receptors CB1 and CB2. CB1 receptors in the striatum mediate profound motor effects when cannabinoids are administered to rodents. Electrophysiological studies suggest CB1 activation can reduce striatal glutamate release, by presynaptic inhibition. We investigated the effects of cannabinoids on glutamate release directly, using superfused striatal slices taken from Sprague Dawley rats. Slices were preloaded with [3H]-glutamic acid and released radioactivity was measured by liquid scintillation counting. Application of a depolarising K+ pulse (40 mM) induced the release of glutamate from striatal slices in a Ca2+-dependent manner. Application of 10μM Δ9-tetrahydrocannabinol (Δ9-THC), a CB1 receptor agonist, significantly reduced (by 44%) the depolarisation-evoked release of [3H]-glutamic acid (P<0.01). The CB1 receptor antagonist SR141716A (3μM) did not effect the depolarisation-evoked release of [3H]-glutamic acid, but blocked the effect...

The endogenous cannabinoid anandamide (N-arachidonylethanolamide) is a long chain fatty acid amide that is capable of activating the cannabinoid receptors similar to Δ9-tetrahydrocannabinol, the active ingredient in marijuana. Anandamide is a putative neurotransmitter with inactivation occurring through a facilitative uptake process with subsequent intracellular metabolism by fatty acid amidohydrolase (FAAH). We propose that FAAH may participate in the anandamide uptake process by creating and maintaining an inward concentration gradient of anandamide. To determine the role of FAAH in anandamide uptake, we have heterologously expressed FAAH cDNA in wild-type HeLa cells. Results demonstrated a lack of FAAH in HeLa cells as determined by RT-PCR of total HeLa RNA and a FAAH enzymatic assay. Interestingly, both wild-type and FAAH-transfected HeLa cells showed similar anandamide transport activity. However, FAAH-transfected HeLa cells had a 3-fold increased ability to metabolize anandamide. Furthermore, the add...