The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders

Isaacson, J. S. & Scanziani, M. How inhibition shapes cortical activity. Neuron 72, 231–243 (2011).

Okun, M. & Lampl, I. Instantaneous correlation of excitation and inhibition during ongoing and sensory-evoked activities. Nat. Neurosci. 11, 535–537 (2008).

Petilla Interneuron Nomenclature, G. et al. Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568 (2008).

Fishell, G. & Rudy, B. Mechanisms of inhibition within the telencephalon: “where the wild things are”. Annu Rev. Neurosci. 34, 535–567 (2011).

London, M. & Hausser, M. Dendritic computation. Annu. Rev. Neurosci. 28, 503–532 (2005).

Wall, N. R. et al. Brain-wide maps of synaptic input to cortical interneurons. J. Neurosci. 36, 4000–4009 (2016).

Kvitsiani, D. et al. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex. Nature 498, 363–366 (2013).

Ji, X. Y. et al. Thalamocortical innervation pattern in mouse auditory and visual cortex: laminar and cell-type specificity. Cereb. Cortex 26, 2612–2625 (2016).

Riedemann, T. Diversity and function of somatostatin-expressing interneurons in the cerebral cortex. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20122952 (2019).

Riedemann, T., Straub, T. & Sutor, B. Two types of somatostatin-expressing GABAergic interneurons in the superficial layers of the mouse cingulate cortex. PLoS ONE 13, e0200567 (2018).

Wang, Y. et al. Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat. J. Physiol. 561, 65–90 (2004).

Silberberg, G. & Markram, H. Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells. Neuron 53, 735–746 (2007).

Adesnik, H., Bruns, W., Taniguchi, H., Huang, Z. J. & Scanziani, M. A neural circuit for spatial summation in visual cortex. Nature 490, 226–231 (2012).

Zhang, S. et al. Selective attention. Long-range and local circuits for top-down modulation of visual cortex processing. Science 345, 660–665 (2014).

Li, L. Y. et al. Differential receptive field properties of parvalbumin and somatostatin inhibitory neurons in mouse auditory cortex. Cereb. Cortex 25, 1782–1791 (2015).

Xu, H., Jeong, H. Y., Tremblay, R. & Rudy, B. Neocortical somatostatin-expressing GABAergic interneurons disinhibit the thalamorecipient layer 4. Neuron 77, 155–167 (2013).

Funk, C. M. et al. Role of somatostatin-positive cortical interneurons in the generation of sleep slow waves. J. Neurosci. 37, 9132–9148 (2017).

Kato, H. K., Gillet, S. N. & Isaacson, J. S. Flexible sensory representations in auditory cortex driven by behavioral relevance. Neuron 88, 1027–1039 (2015).

Adler, A., Zhao, R., Shin, M. E., Yasuda, R. & Gan, W. B. Somatostatin-expressing interneurons enable and maintain learning-dependent sequential activation of pyramidal neurons. Neuron 102, 202–216 e207 (2019).

Kim, D. et al. Distinct roles of parvalbumin- and somatostatin-expressing interneurons in working memory. Neuron 92, 902–915 (2016).

Kamigaki, T. & Dan, Y. Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior. Nat. Neurosci. 20, 854–863 (2017).

Francis, B. H., Baskin, D. G., Saunders, D. R. & Ensinck, J. W. Distribution of somatostatin-14 and somatostatin-28 gastrointestinal-pancreatic cells of rats and humans. Gastroenterology 99, 1283–1291 (1990).

Abdel-Rahman, O., Lamarca, A., Valle, J. W. & Hubner, R. A. Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations. Endocr. Relat. Cancer 21, R485–R493 (2014).

Patel, Y. C. Somatostatin and its receptor family. Front. Neuroendocrinol. 20, 157–198 (1999).

Weiss, R. E., Reddi, A. H. & Nimni, M. E. Somatostatin can locally inhibit proliferation and differentiation of cartilage and bone precursor cells. Calcif. Tissue Int. 33, 425–430 (1981).

Lepousez, G., Mouret, A., Loudes, C., Epelbaum, J. & Viollet, C. Somatostatin contributes to in vivo gamma oscillation modulation and odor discrimination in the olfactory bulb. J. Neurosci. 30, 870–875 (2010).

Song, Y. H. et al. Somatostatin enhances visual processing and perception by suppressing excitatory inputs to parvalbumin-positive interneurons in V1. Sci. Adv. 6, eaaz0517 (2020).

Tasic, B. et al. Shared and distinct transcriptomic cell types across neocortical areas. Nature 563, 72–78 (2018).

Miyoshi, G. et al. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J. Neurosci. 30, 1582–1594 (2010).

Tapia-Arancibia, L., Pares-Herbute, N. & Astier, H. Calcium dependence of somatostatin (SRIF) release and cyclic AMP levels in cultured diencephalic neurons. Neuroendocrinology 49, 555–560 (1989).

Gamse, R. et al. Release of immunoreactive somatostatin from hypothalamic cells in culture: inhibition by gamma-aminobutyric acid. Proc. Natl Acad. Sci. USA 77, 5552–5556 (1980).

Tapia-Arancibia, L. & Astier, H. Actions of excitatory amino acids on somatostatin release from cortical neurons in primary cultures. J. Neurochem. 53, 1134–1141 (1989).

Fontana, G., De Bernardi, R., Ferro, F., Gemignani, A. & Raiteri, M. Characterization of the glutamate receptors mediating release of somatostatin from cultured hippocampal neurons. J. Neurochem. 66, 161–168 (1996).

Rage, F., Rougeot, C. & Tapia-Arancibia, L. GABAA and NMDA receptor activation controls somatostatin messenger RNA expression in primary cultures of hypothalamic neurons. Neuroendocrinology 60, 470–476 (1994).

Cattaneo, S. et al. Somatostatin-expressing interneurons co-release GABA and glutamate onto different postsynaptic targets in the striatum. Preprint at https://www.biorxiv.org/content/10.1101/566984v1 (2019).

Liguz-Lecznar, M., Urban-Ciecko, J. & Kossut, M. Somatostatin and somatostatin-containing neurons in shaping neuronal activity and plasticity. Front. Neural Circuits 10, 48 (2016).

Baraban, S. C. & Tallent, M. K. Interneuron diversity series: interneuronal neuropeptides–endogenous regulators of neuronal excitability. Trends Neurosci. 27, 135–142 (2004).

Bonanno, G., Carita, F., Cavazzani, P., Munari, C. & Raiteri, M. Selective block of rat and human neocortex GABA(B) receptors regulating somatostatin release by a GABA(B) antagonist endowed with cognition enhancing activity. Neuropharmacology 38, 1789–1795 (1999).

Davies, P., Katzman, R. & Terry, R. D. Reduced somatostatin-like immunoreactivity in cerebral cortex from cases of Alzheimer disease and Alzheimer senile dementa. Nature 288, 279–280 (1980).

Ramos, B. et al. Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1 x APP transgenic model of Alzheimer’s disease. Neurobiol. Aging 27, 1658–1672 (2006).

Terry, R. D. & Katzman, R. Senile dementia of the Alzheimer type. Ann. Neurol. 14, 497–506 (1983).

Kumar, U. Expression of somatostatin receptor subtypes (SSTR1-5) in Alzheimer’s disease brain: an immunohistochemical analysis. Neuroscience 134, 525–538 (2005).

Ramos, B. et al. Early neuropathology of somatostatin/NPY GABAergic cells in the hippocampus of a PS1xAPP transgenic model of Alzheimer’s disease. Neurobiol. Aging 27, 1658–1672 (2006).

Fearnley, J. M. & Lees, A. J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5), 2283–2301 (1991).

Wakabayashi, K. et al. The Lewy body in Parkinson’s disease and related neurodegenerative disorders. Mol. Neurobiol. 47, 495–508 (2013).

Braak, H. & Braak, E. Pathoanatomy of Parkinson’s disease. J. Neurol. 247, II3–II10 (2000). Suppl 2.

Epelbaum, J. et al. Somatostatin and dementia in Parkinson’s disease. Brain Res. 278, 376–379 (1983).

Iwasawa, C. et al. Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with parkin mutations. Mol. Brain 12, 5 (2019).

McGregor, M. M. & Nelson, A. B. Circuit mechanisms of Parkinson’s disease. Neuron 101, 1042–1056 (2019).

Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Prim. 1, 15005 (2015).

Waldvogel, H. J., Kim, E. H., Tippett, L. J., Vonsattel, J. P. & Faull, R. L. The neuropathology of Huntington’s disease. Curr. Top. Behav. Neurosci. 22, 33–80 (2015).

Bolam, J. P., Hanley, J. J., Booth, P. A. & Bevan, M. D. Synaptic organisation of the basal ganglia. J. Anat. 196(Pt 4), 527–542 (2000).

Holley, S. M., Galvan, L., Kamdjou, T., Cepeda, C. & Levine, M. S. Striatal GABAergic interneuron dysfunction in the Q175 mouse model of Huntington’s disease. Eur. J. Neurosci. 49, 79–93 (2019).

Holley, S. M. et al. Enhanced GABAergic inputs contribute to functional alterations of cholinergic interneurons in the R6/2 mouse model of Huntington’s disease. eNeuro https://doi.org/10.1523/ENEURO.0008-14.2015 (2015).

Rajput, P. S. et al. Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington’s disease transgenic mice. PLoS ONE 6, e24467 (2011).

Kremer, H. P., Roos, R. A., Dingjan, G., Marani, E. & Bots, G. T. Atrophy of the hypothalamic lateral tuberal nucleus in Huntington’s disease. J. Neuropathol. Exp. Neurol. 49, 371–382 (1990).

Murrough, J. W., Iacoviello, B., Neumeister, A., Charney, D. S. & Iosifescu, D. V. Cognitive dysfunction in depression: neurocircuitry and new therapeutic strategies. Neurobiol. Learn Mem. 96, 553–563 (2011).

Disner, S. G., Beevers, C. G., Haigh, E. A. & Beck, A. T. Neural mechanisms of the cognitive model of depression. Nat. Rev. Neurosci. 12, 467–477 (2011).

Rubinow, D. R., Gold, P. W., Post, R. M. & Ballenger, J. C. CSF somatostatin in affective illness and normal volunteers. Prog. Neuropsychopharmacol. Biol. Psychiatry 9, 393–400 (1985).

Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23, 477–501 (2000).

Seney, M. L., Tripp, A., McCune, S., Lewis, D. A. & Sibille, E. Laminar and cellular analyses of reduced somatostatin gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiol. Dis. 73, 213–219 (2015).

Guilloux, J. P. et al. Molecular evidence for BDNF- and GABA-related dysfunctions in the amygdala of female subjects with major depression. Mol. Psychiatry 17, 1130–1142 (2012).

Tripp, A., Kota, R. S., Lewis, D. A. & Sibille, E. Reduced somatostatin in subgenual anterior cingulate cortex in major depression. Neurobiol. Dis. 42, 116–124 (2011).

Seney, M. L. et al. The role of genetic sex in affect regulation and expression of GABA-related genes across species. Front. Psychiatry 4, 104 (2013).

Leucht, S. et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 382, 951–962 (2013).

Lodge, D. J. & Grace, A. A. Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharm. Sci. 32, 507–513 (2011).

Konradi, C. et al. Hippocampal interneurons are abnormal in schizophrenia. Schizophr. Res. 131, 165–173 (2011).

Reinikainen, K. J., Koponen, H., Jolkkonen, J. & Riekkinen, P. J. Decreased somatostatin-like immunoreactivity in the cerebrospinal fluid of chronic schizophrenic patients with cognitive impairment. Psychiatry Res. 33, 307–312 (1990).

Hoftman, G. D. et al. Altered cortical expression of GABA-related genes in schizophrenia: illness progression vs developmental disturbance. Schizophr. Bull. 41, 180–191 (2015).

Bristow, G. C. et al. 16p11 duplication disrupts hippocampal-orbitofrontal-amygdala connectivity, revealing a neural circuit endophenotype for schizophrenia. Cell Rep. 31, 107536 (2020).

Vécsei, L., Bollók, I. & Telegdy, G. Intracerebroventricular somatostatin attenuates electroconvulsive shock-induced amnesia in rats. Peptides 4, 293–295 (1983).

Craft, S. et al. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch. Gen. Psychiatry 56, 1135–1140 (1999).

Iwata, N., Takaki, Y., Fukami, S., Tsubuki, S. & Saido, T. C. Region-specific reduction of a beta-degrading endopeptidase, neprilysin, in mouse hippocampus upon aging. J. Neurosci. Res. 70, 493–500 (2002).

Leissring, M. A. et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087–1093 (2003).

Iwata, N. et al. Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain. J. Neurosci. 24, 991–998 (2004).

Saito, T. et al. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat. Med. 11, 434–439 (2005).

Savonenko, A. et al. Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol. Dis. 18, 602–617 (2005).

Drechsel, D. N., Hyman, A. A., Cobb, M. H. & Kirschner, M. W. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol. Biol. Cell 3, 1141–1154 (1992).

Busciglio, J., Lorenzo, A., Yeh, J. & Yankner, B. A. β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14, 879–888 (1995).

Hanger, D. P., Anderton, B. H. & Noble, W. Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol. Med. 15, 112–119 (2009).

Wang, J. Z., Grundke-Iqbal, I. & Iqbal, K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur. J. Neurosci. 25, 59–68 (2007).

de Lecea, L. Cortistatin—functions in the central nervous system. Mol. Cell Endocrinol. 286, 88–95 (2008).

Sanchez-Alavez, M. et al. Cortistatin modulates memory processes in rats. Brain Res. 858, 78–83 (2000).

Yang, L. P. & Keating, G. M. Octreotide long-acting release (LAR): a review of its use in the management of acromegaly. Drugs 70, 1745–1769 (2010).

Hu, M. & Tomlinson, B. Pharmacokinetic evaluation of lanreotide. Expert Opin. Drug Metab. Toxicol. 6, 1301–1312 (2010).

Bruns, C., Lewis, I., Briner, U., Meno-Tetang, G. & Weckbecker, G. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrinol. 146, 707–716 (2002).

Chalabi, M. et al. Somatostatin analogs: does pharmacology impact antitumor efficacy? Trends Endocrinol. Metab. 25, 115–127 (2014).

Melmed, S. New therapeutic agents for acromegaly. Nat. Rev. Endocrinol. 12, 90–98 (2016).

Wildemberg, L. E. & Gadelha, M. R. Pasireotide for the treatment of acromegaly. Expert Opin. Pharmacother. 17, 579–588 (2016).

Drewe, J., Fricker, G., Vonderscher, J. & Beglinger, C. Enteral absorption of octreotide: absorption enhancement by polyoxyethylene-24-cholesterol ether. Br. J. Pharm. 108, 298–303 (1993).

Fricker, G. et al. Phospholipids and lipid-based formulations in oral drug delivery. Pharm. Res. 27, 1469–1486 (2010).

Banks, W. A. & Kastin, A. J. Peptides and the blood-brain barrier: lipophilicity as a predictor of permeability. Brain Res. Bull. 15, 287–292 (1985).

Banks, W. A. et al. Permeability of the murine blood-brain barrier to some octapeptide analogs of somatostatin. Proc. Natl Acad. Sci. USA 87, 6762–6766 (1990).

Wong, H. L., Wu, X. Y. & Bendayan, R. Nanotechnological advances for the delivery of CNS therapeutics. Adv. Drug Deliv. Rev. 64, 686–700 (2012).

Spindler, K. R. & Hsu, T.-H. Viral disruption of the blood–brain barrier. Trends Microbiol. 20, 282–290 (2012).

Alexander, A. et al. Recent expansions of novel strategies towards the drug targeting into the brain. Int. J. Nanomed. 14, 5895 (2019).

Kaur, I. P., Bhandari, R., Bhandari, S. & Kakkar, V. Potential of solid lipid nanoparticles in brain targeting. J. Control Release 127, 97–109 (2008).

Pahuja, R. et al. Trans-blood brain barrier delivery of dopamine-loaded nanoparticles reverses functional deficits in parkinsonian rats. ACS Nano 9, 4850–4871 (2015).

Zeng, H. et al. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell 149, 483–496 (2012).