Somatostatinergic systems in brain: Networks and functions

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Abstract

Somatostatin is abundantly expressed in mammalian brain. The peptide binds with high affinity to six somatostatin receptors, sst1, sst2A and B, sst3 to 5, all belonging to the G-protein-coupled receptor family. Recent advances in the neuroanatomy of somatostatin neurons and cellular distribution of sst receptors shed light on their functional roles in the neuronal network. Beside their initially described neuroendocrine role, somatostatin systems subserve neuromodulatory roles in the brain, influencing motor activity, sleep, sensory processes and cognitive functions, and are altered in brain diseases like affective disorders, epilepsia and Alzheimer's disease.

Introduction

Somatostatin14 (SRIF: somatotropin release inhibiting factor) was serendipituously discovered in 1972 by Roger Guillemin and his colleagues who were trying to purify and characterize growth hormone (GH)-releasing hormone (GHRH) (Brazeau et al., 1973). Soon thereafter, an amino-terminally extended peptide, SRIF28, was purified from the gut. Both peptides were found in the nervous system, where SRIF14 is the predominant form (for review, Epelbaum, 1986). Using iodinated somatostatinergic ligands, two pharmacologically distinct binding sites were found in the brain. Later, six somatostatin receptor (sst) subtypes, named sst1, sst2A, sst2B, sst3, sst4 and sst5, and belonging to the G-protein-coupled receptor family, were cloned and divided into two subfamilies, based on their pharmacological and molecular characteristics (for review, see Hannon et al., 2004, Olias et al., 2004). Many transduction mechanisms have been described in transfected systems (for review see Lahlou et al., 2004, Olias et al., 2004), however most physiological actions of the native receptors in situ remain to be established. The generation of specific antibodies against each somatostatin receptor revealed a definite cellular and subcellular localization of somatostatin receptor subtypes in the central nervous system (CNS). The development of specific somatostatin analogues and antagonists (Hannon et al., 2004, Engström et al., 2006) together with the availability of genetically modified animal models (Allen et al., 2003, Kreienkamp et al., 1999, Strowski et al., 2003, Videau et al., 2003, Zeyda et al., 2001, Zheng et al., 1997) contributed to a better understanding of the individual somatostatin receptor characteristics in vivo, and their specific roles in brain functioning. This review summarizes the latest advances concerning the anatomical and functional characterization of central somatostatinergic networks as well as their physiopathological implications in CNS diseases.

Section snippets

Central somatostatinergic systems

SRIF-immunoreactivity is found in many neurons in the mammalian brain including humans. High immunoreactivity is found in the mediobasal hypothalamus and median eminence, amygdala, preoptic area, hippocampus, striatum, cerebral cortex, olfactory regions, and the brainstem. Two main categories of somatostatinergic neurons can be distinguished: those which project to a distance from their soma (long-projecting neurons) and short GABAergic neurons (interneurons) acting within microcircuits.

Biological roles of somatostatin

Based on its coexistence in neurons with classical neurotransmitters, its release properties and its capacity to modulate synaptic transmission and neuronal activity, somatostatin is considered as a neuromodulatory agent in the central nervous system. Acting through sst2 and given coexpressed subtypes, the peptide leads to physiological actions mediating motor, cognitive and sensory effects.

Physiopathological implications of central somatostatinergic systems

Long acting sst2-preferring agonists, such as octreotide and lanreotide, are widely used for the clinical management of acromegalic patients, gastroenterological or pancreatic tumours and other gastrointestinal disorders. Modified analogs are also developed for tumour imaging and radiotherapy. Not surprisingly, therapeutic applications for neuropsychiatric diseases still need to be established. Nevertheless, changes in somatostatin and sst receptors have long been associated with dementia,

Conclusions and perspectives

Thirty-five years after its discovery, somatostatin can be considered as a “successful” neuroendocrine peptide. Long-acting agonists have been used for more than 18 years in clinics for the management of GH/IGF-1 hypersecretion and tumour size in patients with GH-secreting pituitary adenoma responsive to sst-agonist therapy (Maiza et al., 2007). Nevertheless, the wide distribution of somatostatin systems throughout nearly all brain regions suggests that they play major roles in brain

Acknowledgments

The authors wish to thank Drs. Annie Slama and Eric Maubert for experimental assistance, Pr. Graeme Bell for providing the msstr2 plasmid and Alice Cougnon for assistance with the rodent colony maintenance.

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