neuropeptide-y and Brain-Diseases

Interneurons are often classified according to neuropeptide content. However, it is becoming increasingly clear that neuropeptides are more than convenient neurochemical markers and can act as important modulators of neuronal activity. Recent advances in understanding neuropeptide release and physiological actions suggest that the interneuronal system of neuropeptides is crucial for maintaining appropriate brain function under normal and pathophysiological conditions. In particular, interneuronal neuropeptides appear to play roles in cognition and as endogenous anti-epileptic agents. This article describes current understanding of the conditions under which neuropeptides are released from interneurons, their specific effects on neuronal excitability and synaptic transmission, and the consequences of their loss of function.

Topics: Animals; Brain; Brain Diseases; Epilepsy; Interneurons; Neural Inhibition; Neuropeptide Y; Neuropeptides; Somatostatin; Synaptic Transmission

In schizophrenia, glutamic acid decarboxylase 1 (GAD1) disturbances are robust, consistently observed, cell-type specific and represent a core feature of the disease. In addition, neuropeptide Y (NPY), which is a phenotypic marker of a sub-population of GAD1-containing interneurons, has shown reduced expression in the prefrontal cortex in subjects with schizophrenia, suggesting that dysfunction of the NPY+ cortical interneuronal sub-population might be a core feature of this devastating disorder. However, modeling gene expression disturbances in schizophrenia in a cell type-specific manner has been extremely challenging. To more closely mimic these molecular and cellular human post-mortem findings, we generated a transgenic mouse in which we downregulated GAD1 mRNA expression specifically in NPY+ neurons. This novel, cell type-specific in vivo system for reducing gene expression uses a bacterial artificial chromosome (BAC) containing the NPY promoter-enhancer elements, the reporter molecule (eGFP) and a modified intron containing a synthetic microRNA (miRNA) targeted to GAD1. The animals of isogenic strains are generated rapidly, providing a new tool for better understanding the molecular disturbances in the GABAergic system observed in complex neuropsychiatric disorders such as schizophrenia. In the future, because of the small size of the silencing miRNAs combined with our BAC strategy, this method may be modified to allow generation of mice with simultaneous silencing of multiple genes in the same cells with a single construct, and production of splice-variant-specific knockdown animals.

Topics: Alternative Splicing; Animals; Brain Diseases; Chromosomes, Artificial, Bacterial; Disease Models, Animal; Gene Expression Regulation; Gene Silencing; Glutamate Decarboxylase; HEK293 Cells; Humans; Mice; Mice, Transgenic; MicroRNAs; Neuropeptide Y; Schizophrenia

Brain-derived neurotrophic factor (BDNF) has been reported to be critical for the development of cortical inhibitory neurons. However, the effect of BDNF on the expression of transcripts whose protein products are involved in gamma amino butric acid (GABA) neurotransmission has not been assessed. In this study, gene expression profiling using oligonucleotide microarrays was performed in prefrontal cortical tissue from mice with inducible deletions of BDNF. Both embryonic and adulthood ablation of BDNF gave rise to many shared transcriptome changes. BDNF appeared to be required to maintain gene expression in the SST-NPY-TAC1 subclass of GABA neurons, although the absence of BDNF did not alter their general phenotype as inhibitory neurons. Furthermore, we observed expression alterations in genes encoding early-immediate genes (ARC, EGR1, EGR2, FOS, DUSP1, DUSP6) and critical cellular signaling systems (CDKN1c, CCND2, CAMK1g, RGS4). These BDNF-dependent gene expression changes may illuminate the biological basis for transcriptome changes observed in certain human brain disorders.

Topics: Animals; Brain Diseases; Brain-Derived Neurotrophic Factor; Crosses, Genetic; Doxycycline; gamma-Aminobutyric Acid; Gene Expression Profiling; Gene Expression Regulation, Developmental; Genes, Immediate-Early; Humans; Immediate-Early Proteins; Interneurons; Intracellular Signaling Peptides and Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Oligonucleotide Array Sequence Analysis; Organ Specificity; Phenotype; Prefrontal Cortex; Recombinant Fusion Proteins; Sequence Deletion; Somatostatin; Time Factors; Transcription, Genetic

We examined the effect of streptozotocin-induced maternal diabetes of 6-day duration and 4- to 24-h intracerebroventricular and systemic hyperinsulinism on fetal brain neuropeptide Y (NPY) synthesis and concentrations. Maternal diabetes (n = 6) leading to fetal hyperglycemia (5-fold increase; P < 0.05) and normoinsulinemia caused a 40% decline (P < 0.05) in fetal brain NPY messenger RNA (mRNA) and a 50% decline (P < 0.05) in NPY radioimmunoassayable levels compared to levels in streptozotocin-treated nondiabetic (n = 7) and vehicle-treated control (n = 8) animals. In contrast, systemic hyperinsulinemia (n = 7) of 5- to 100-fold increase (P < 0.05) over the respective control (n = 7) with normoglycemia caused an insignificant (20-30%) decrease in fetal brain NPY mRNA and protein concentrations. However, fetal intracerebroventricular hyperinsulinism (n = 7) with no change in fetal glucose concentrations caused a 50-60% decline (P < 0.05) in only the NPY peptide levels, with no change in the corresponding mRNA amounts. We conclude that fetal hyperglycemia of 6-day duration and intracerebroventricular hyperinsulinism of 4-24 h suppress fetal brain NPY concentrations, the former by a pretranslational and the latter by either a translational/posttranslational mechanism or depletion of intracellular secretory stores. We speculate that fetal hyperglycemia and intracerebroventricular hyperinsulinism additively can inhibit various intrauterine and immediate postnatal NPY-mediated biological functions.

Topics: Acute Disease; Animals; Brain; Brain Diseases; Female; Fetal Diseases; Fetus; Hyperglycemia; Hyperinsulinism; Neuropeptide Y; Osmolar Concentration; Pregnancy; Pregnancy in Diabetics; Rats; Rats, Sprague-Dawley

Perivascular innervation in cerebral arteries of spontaneously hypertensive rats and of normotensive Wistar-Kyoto rats was studied. Adrenergic nerve fibers and neuropeptide Y-containing nerve fibers, indicative of vasoconstrictor nerves, were denser in all cerebral arteries of spontaneously hypertensive rats than those of Wistar-Kyoto rats. In contrast, cholinergic nerve fibers and vasoactive intestinal polypeptide, substance P-containing nerve fibers, indicative of vasodilator nerves, remained unchanged in all cerebral arteries of spontaneously hypertensive rats, as compared with findings in the Wistar-Kyoto rats. Thus, not only adrenergic nerve fibers but also neuropeptide Y-containing nerve fibers may play an important role in preventing the disruption of the blood-brain barrier and the development of hypertensive encephalopathy in spontaneously hypertensive rats.

Topics: Adrenergic Fibers; Animals; Brain Diseases; Cerebral Arteries; Cholinergic Fibers; Hypertension; Immunohistochemistry; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Substance P; Vasoactive Intestinal Peptide; Vasoconstriction; Vasodilation

Neuropeptide Y (NPY) was measured in central and peripheral cerebrospinal fluid (CSF) in patients suffering from various intracranial disorders. The central NPY-like immunoreactivity (LI) level showed a concentration of 129 +/- 19 pmol.l-1 and was significantly increased (p less than 0.05) compared to peripheral CSF (73 +/- 9 pmol.l-1). From five patients with subarachnoid haemorrhage the CSF NPY-LI levels reached 154 +/- 47 pmol.l-1. In five patients peripheral and central CSF was collected at the same occasion and the CSF NPY-LI concentration was 76 +/- 17 pmol.l-1 in peripheral and 142 +/- 23 pmol.l-1 in central CSF (p less than 0.01), respectively. In a reference group of 9 patients, who were examined by lumbar myelography because of suspected intervertebral herniated discs, the peripheral CSF NPY-LI concentration was 59 +/- 5 pmol.l-1 a value which was also significantly lower compared to NPY-LI levels in central CSF. Thus it is obvious that NPY is present in human CSF with a relatively higher concentration in central than in peripheral CSF at least in patients with disorders of the central nervous system, suggesting a central origin of the NPY.

Topics: Brain Diseases; Brain Neoplasms; Humans; Intervertebral Disc Displacement; Neuropeptide Y

The distribution of neuropeptide Y-like immunoreactivity (NPY-LI) within the rat basal ganglia was studied using microdissection with a sensitive radioimmunoassay, and excitotoxin lesions were made in an attempt to characterise the neurones containing NPY in this brain area. Immunoreactivity was unevenly distributed in the basal ganglia of control rats, with concentrations in the caudate-putamen (CP) and nucleus accumbens being appreciably higher than those found in the globus pallidus and substantia nigra (SN). Within the CP, immunoreactivity was concentrated in caudal and extreme rostral aspects. N-Methyl-D-aspartate lesions of the rostral CP significantly reduced immunoreactivity in this area, whilst levels in other regions of the basal ganglia were unaffected. Neurones containing NPY-LI are likely to be intrinsic to the CP and do not appear to project to the globus pallidus or SN.

Topics: Animals; Aspartic Acid; Basal Ganglia; Brain Diseases; Caudate Nucleus; Male; N-Methylaspartate; Nerve Tissue Proteins; Neuropeptide Y; Putamen; Radioimmunoassay; Rats; Rats, Inbred Strains; Tissue Distribution