Characterization of inositol monophosphatase in human cerebrospinal fluid

Inositol monophosphatase (IMPase) has been identified and characterized in human lumbar cerebrospinal fluid (CSF). The CSF enzyme has aK_m for inositol 1-phosphate (Ins(1)P; 0.12 mM), a magnesium dependence (optimum concentration 10 mM) and a sensitivity to inhibition by either the bisphosphonate inhibitor 1-(4-hydroxyphenyloxy)ethane-1,1-bisphosphonic acid (L-690,330) or LiCl (IC₅₀'s: 1.3 μM and 1.6 mM, respectively) similar to native human brain and human recombinant enzymes. In CSF, antiserum raised against purified bovine brain IMPase recognised a protein of 30 kDa, identical to that seen in human brain homogenate. It remains to be determined whether CSF IMPase activity may be a useful in vivo marker of CNS phosphatidyl inositol cycle activity in disorders where this signalling pathway may be altered (e.g. manic depression).     

Inositol monophosphatase, the putative therapeutic target for lithium

Lithium has been hypothesised to exert its therapeutic effects in the treatment of bipolar disorder by attenuating phosphatidylinositol (PI) cell signalling pathways that are presumably hyperactive in this disorder. More specifically, lithium has been proposed to inhibit inositol monophosphatase (IMPase) thereby causing a depletion of intracellular inositol which results in a reduction in the synthesis of the PI required to sustain this signalling pathway. In the present article this ‘inositol depletion’ hypothesis will be reviewed and pathological, pharmacodynamic, developmental and anatomical aspects of IMPase as well as inhibitors of this enzyme will be described.     

Chronic dietary lithium induces increased levels of myo-inositol-1-phosphatase activity in rat cerebral cortex homogenates

The monovalent lithium ion inhibits the enzyme myo-inositol-1-phosphatase at concentrations comparable to those which are useful in the treatment of manic depressive illness. However, dialyzed cortical homogenates from rats which have been fed diets containing lithium carbonate demonstrate increased myo-inositol-1-phosphate phosphatase activity. Over a 4-week period, there is an approximate doubling of the lithium-sensitive myo-inositol-1-phosphatase activity in the homogenate.     

Development of Purkinje cells in humans: an immunohistochemical study using a monoclonal antibody against the inositol 1, 4, 5-triphosphate type 1 receptor (IP3R1)

Immunohistochemical analyses were carried out on the Purkinje cells from 21 autopsied fetal and early postnatal normal cerebella using a monoclonal antibody against the inositol 1, 4, 5-triphosphate type 1 receptor (IP₃R1) as a cytochemical marker of Purkinje cells. In normal adult cerebella used as positive controls, the cell bodies, axons, and dendrites, including spiny branchlets of the Purkinje cells, were specifically stained by the antibody. In the fetal cerebella examined, the IP₃R1 immunoreactivity was first detected in the soma of multilayered cells just beneath the molecular layer at 16 weeks of gestation. The IP₃R1 immunoreactivity gradually increased in area of positive staining from soma to dendrites and spiny branchlets, and the dendritic outgrowth rapidly progressed during 6 months after birth. The Purkinje cell maturation was more advanced in the vermis than in the hemisphere, more in the posterior lobe than in the anterior lobe, and more at the bottom of the folia than at the top. Partial absence of the Purkinje cells in the cerebellar cortex was observed in three cases. Heterotopias including Purkinje cells were often noted in the cerebellar white matter in five cases. Received: 8 October 1998 / Revised, accepted: 11 January 1999     

Activation of a non-specific cation conductance by intracellular injection of inositol 1,3,4,5-tetrakisphosphate into identified neurons of Aplysia

The ionic mechanism of the effect of intracellulary injected inositol 1,3,4,5-tetrakisphosphate (IP₄) on the membrane of identified neurons (R9–R12) of Aplysia kurodai was investigated with conventional voltage-clamp, pressure injection, and ion-substitution techniques. Intracellular injection of IP₄ into a neuron voltage-clamped at −45 mV reproducibly induced a slow inward current (20–60 s in duration, 3–5 nA in amplitude) associated with a conductance increase. The current was decreased by depolarization and increased by hyperpolarization. The extrapolated reversal potential was −21 mV. The IP₄-induced inward current was sensitive to changes in the external Na⁺, Ca²⁺ and K⁺ concentration but not to changes in Cl⁻ concentration, and was resistant to tetrodotoxin (50 μM). When the cell was perfused with tetraethylammonium (5 mM) but not with 4-aminopyridine (5 mM), the IP₄-induced inward current recorded at −45 mV slightly increased. The IP₄-induced inward current was partially reduced by calcium channel blockers (Co²⁺ and Mn²⁺). These results suggest that intracellularly injected IP₄ can activate a non-specific cation conductance.     

Noradrenaline-stimulated inositol phospholipid breakdown as a measure of alpha1-adrenoceptor function in rat hippocampal miniprisms after repeated antidepressant treatment

Summary Noradrenaline-stimulated inositol phospholipid (PI) breakdown in rat hippocampal miniprisms was used as a measure of alpha₁-adrenoceptor function after repeated antidepressant treatment. After 24–29 days of oral treatment with either desipramine, mianserin, maprotiline or zimeldine (all at doses of 10 mg/kg b.i.d.), there was no significant difference in the degree of stimulation of hippocampal PI breakdown by 0.4, 2, 10 or 100M nor-adrenaline. It is concluded that there is no supersensitivity of hippocampal alpha₁-adrenoceptors coupled to PI breakdown after repeated antidepressant treatment under the conditions used.     

Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement

In recent years, with advances in molecular genetics, many new mutations with various ataxic syndromes have been identified. Recently, homozygous sequestosome 1 (SQSTM1) gene variant with a progressive childhood-onset cerebellar ataxia, dystonia and gaze palsy was described. Here we describe a patient with progressive cerebellar ataxia and gaze palsy, as well as myoclonus, cognitive impairment and growth retardation with a homozygous SQSTM1 variant NM_003900.5:c.55G > T (p.Glu19*). Our case had brainstem lesions on brain magnetic resonance imaging that have not been previously reported. This novel finding expands the SQSTM1 gene-associated neuroradiologic spectrum. Homozygous SQSTM1 variant should be considered in the differential diagnosis in patients presenting with cerebellar findings, gaze palsy, and cognitive impairment to facilitate early diagnosis and genetic counseling.     

Missing link identified: GpBAR1 is a neuronal bile acid receptor

Abstract In addition to their classical functions in aiding the digestion and absorption of lipids, bile acids are increasingly gaining appreciation for their roles in regulating intestinal physiology. Bile acids are now widely considered as hormones that exert a wide range of physiological and pathophysiological effects both within and outside the gastrointestinal (GI) tract. The discovery of the bile acid receptor, GpBAR1, represented a major step forward in our understanding of how cells can sense and respond to bile acids. GpBAR1 is a cell surface G protein‐coupled receptor expressed on adipose tissue and skeletal muscle where it has been found to be an important regulator of cellular metabolism. In a paper published in the current issue of Neurogastroenterology and Motility, Poole et al. investigated the expression and function of GpBAR1 in mouse intestine. They found the receptor to be expressed throughout the GI tract but predominantly on nerves within the myenteric and submucosal plexuses. Employing in vitro and in vivo techniques they demonstrated that activation of GpBAR1 by bile acids inhibits small and large intestinal motor function and delays intestinal transit. The effects of GpBAR1 activation are mediated through activation of cholinergic and nitrergic interneurons. The data reported by Poole et al. provides novel and exciting insights into how bile acids exert their actions in the intestine. This Editorial Viewpoint aims to further consider the potential physiological and pathophysiological implications of their findings.     

Neuroleptic Drugs and 5HT1 Receptor:Different Potencies of Various Neuroleptic Drugs on 5HT1 Receptors in Discrete Regions of the Rat Brain

Abstract: The potencies of various neuroleptic drugs (zotepine, chlorpromazine-HCl, haloperidol and spiperone) on serotonin, (5HT₁) receptors were examined in discrete rat brain regions using the radio receptor assay. The potencies of the neuroleptic drugs on 5HT₁ receptors were clearly differentiated in the discrete brain regions:zotepine was the most potent in the frontal cortex, striatum and brain stem; spiperone was the most potent in the hippocampus. Furthermore, zotepine and chlorpromazine-HCl produced no great differences among the various regional 5HT₁ receptors, while butyrophenones, haloperidol and spiperone showed remarkable differences. These findings demonstrate that the neuroleptic drugs can be differentiated according to their different affinities for regionally discrete 5HT, receptors in the brain. This suggests that 5HT₁ receptors may be able to be classified into two subtypes:the zotepine and chlorpromazine-HCl group having a high affinity for one subtype and butyrophenones a high affinity for the other.     

Dystonia as a presenting sign of spinocerebellar ataxia type 1.

We report on a 39-year-old man who presented initially with marked blepharospasm, oromandibular dystonia and retrocollis and one year later developed mild ataxia. Our findings suggest that dystonia can be a disabling presenting sign of SCA1 and support the clinical heterogeneity of SCA1, highlighting the importance of considering this entity in patients combining dystonia and cerebellar ataxia.     

Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.     

Deep Brain Stimulation of the Globus Pallidus in a 7-Year-Old Girl with DYT1 Generalized Dystonia

The experience of pediatric deep brain stimulation (DBS) of the globus pallidus internus (GPi) in the treatment of early-onset DYT1 generalized dystonia is still limited. Here, we report the surgical experience of bilateral GPi-DBS under general anesthesia by using microelectrode recording in a 7-year-old girl with early-onset DYT1 generalized dystonia. Excellent improvement of her dystonia without neurological complications was achieved. This case report demonstrates that GPi-DBS is an effective and safe method for the treatment of medically refractory early-onset DYT1 generalized dystonia in children.     

Identification of BiP as a CB1 Receptor-Interacting Protein That Fine-Tunes Cannabinoid Signaling in the Mouse Brain

Cannabinoids, the bioactive constituents of cannabis, exert a wide array of effects on the brain by engaging Type 1 cannabinoid receptor (CB₁R). Accruing evidence supports that cannabinoid action relies on context-dependent factors, such as the biological characteristics of the target cell, suggesting that cell population-intrinsic molecular cues modulate CB₁R-dependent signaling. Here, by using a yeast two-hybrid-based high-throughput screening, we identified BiP as a potential CB₁R-interacting protein. We next found that CB₁R and BiP interact specifically in vitro, and mapped the interaction site within the CB₁R C-terminal (intracellular) domain and the BiP C-terminal (substrate-binding) domain-α. BiP selectively shaped agonist-evoked CB₁R signaling by blocking an “alternative” G_q/11 protein-dependent signaling module while leaving the “classical” G_i/o protein-dependent inhibition of the cAMP pathway unaffected. In situ proximity ligation assays conducted on brain samples from various genetic mouse models of conditional loss or gain of CB₁R expression allowed to map CB₁R-BiP complexes selectively on terminals of GABAergic neurons. Behavioral studies using cannabinoid-treated male BiP^+/− mice supported that CB₁R-BiP complexes modulate cannabinoid-evoked anxiety, one of the most frequent undesired effects of cannabis. Together, by identifying BiP as a CB₁R-interacting protein that controls receptor function in a signaling pathway- and neuron population-selective manner, our findings may help to understand the striking context-dependent actions of cannabis in the brain.SIGNIFICANCE STATEMENT Cannabis use is increasing worldwide, so innovative studies aimed to understand its complex mechanism of neurobiological action are warranted. Here, we found that cannabinoid CB₁ receptor (CB₁R), the primary molecular target of the bioactive constituents of cannabis, interacts specifically with an intracellular protein called BiP. The interaction between CB₁R and BiP occurs selectively on terminals of GABAergic (inhibitory) neurons, and induces a remarkable shift in the CB₁R-associated signaling profile. Behavioral studies conducted in mice support that CB₁R-BiP complexes act as fine-tuners of anxiety, one of the most frequent undesired effects of cannabis use. Our findings open a new conceptual framework to understand the striking context-dependent pharmacological actions of cannabis in the brain.     

TGF‐β1 Pathway as a New Target for Neuroprotection in Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that affects more than 37 million people worldwide. Current drugs for AD are only symptomatic, but do not interfere with the underlying pathogenic mechanisms of the disease. AD is characterized by the presence of ß‐amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. The identification of the molecular determinants underlying AD pathogenesis is a fundamental step to design new disease‐modifying drugs. Recently, a specific impairment of transforming‐growth‐factor‐β1 (TGF‐β1) signaling pathway has been demonstrated in AD brain. The deficiency of TGF‐β1 signaling has been shown to increase both Aβ accumulation and Aβ‐induced neurodegeneration in AD models. The loss of function of TGF‐ß1 pathway seems also to contribute to tau pathology and neurofibrillary tangle formation. Growing evidence suggests a neuroprotective role for TGF‐β1 against Aβ toxicity both in vitro and in vivo models of AD. Different drugs, such as lithium or group II mGlu receptor agonists are able to increase TGF‐β1 levels in the central nervous system (CNS), and might be considered as new neuroprotective tools against Aβ‐induced neurodegeneration. In the present review, we examine the evidence for a neuroprotective role of TGF‐β1 in AD, and discuss the TGF‐β1 signaling pathway as a new pharmacological target for the treatment of AD.