Cortistatin modulates memory processes in rats

Abstract

Cortistatin (CST) is a recently described neuropeptide with high structural homology with somatostatin. Its mRNA is restricted to gamma amino butyric acid (GABA)-containing cells in the cerebral cortex and hippocampus. CST modulates the electrophysiology of the hippocampus and cerebral cortex of rats; hence, it may be modulating mnemonic processes. In this study, we have evaluated the effect of CST and somatostatin (SS) on short- and long-term memory (STM and LTM, respectively), as well as on the extinction of the behavior by using the footshock passive avoidance behavioral test. In addition, we tested the ability of both neuropeptides to affect the generation of cAMP in hippocampal neurons in culture. Results showed that the administration of either CST or SS into the hippocampal CA1 deteriorates memory consolidation in a dose–response fashion and facilitates the extinction of the learned behavior. CST was more potent than SS. Likewise, CST increases cAMP while SS decreases it. These results strongly support a modulatory role for CST in memory processes.

Introduction

Memory is a series of cognitive processes whose neurochemical control is highly complex [26]. For example, in the hippocampus, a cerebral structure crucially involved in the memory network 25, 28, at least three neurotransmitters are regulating its activity, i.e., glutamate (Glu) 15, 21, acetylcholine (ACh) [11]and gamma amino butyric acid (GABA) 2, 27. Glu and ACh enhance hippocampal excitability and exert a facilitating effect on memory 11, 24; whereas GABA depresses hippocampal excitability [27]and facilitates memory extinction 2, 6. In addition, a series of neuropeptides are also involved in this regulation, i.e., somatostatin (SS) and vasoactive intestinal polypeptide (VIP). Both SS and VIP seem to modulate cholinergic activity, and memory processes 10, 16, 17. On the other hand, cAMP has been associated with learning and memory in several animal preparations [19], and its disregulation causes learning and memory deterioration.

Cortistatin (CST) is a neuropeptide recently described in rat [7]and human brains 8, 14. Its mRNA was detected in the brain of rats but not in other organs such as liver or testis [7]. This peptide exhibits an exclusive cortical and hippocampal distribution. Due to the fact that CST mRNA cohybridizes with GAD67 mRNA in the hippocampus, we believe it is synthesized, stored and released by GABAergic cells [9]. CST's active form is conformed by 14 amino acids (aa). Its aa sequence shows a high structural homology with SS-14. Both molecules share 11 aa. CST binds all five SS receptors with high affinity (pM range) [23]; therefore, we expect it to induce effects similar to those produced by SS. Accordingly, it produces similar hyperpolarizing effects as SS on hippocampal pyramidal cells in in vitro preparations; however, this effect lasts longer [7]. In contrast, there are several other effects caused by CST that seem to go in an opposite direction. For example, CST reduces the ACh excitatory action in the hippocampus while SS facilitates it [7]. In this context, CST seems to be a neuropeptide with potential anticholinergic antagonizing effects. This CST effect may be mediated by SS receptors, or, alternatively, by its own receptors (to be described) or by facilitating GABA activity. In addition, a recent report has indicated that CST may be inhibiting locus coeruleus (LC) neurons, which are mainly noradrenergic cells, by facilitating K⁺ conductance [5].

Consistent with CST's inhibitory effects on hippocampal activity, a recently published study has suggested that CST may be regulating memory processes in mice [12]. In this context, the goal of this study is to assess if CST actually plays a role in memory regulation. In order to reach this goal, we decided to investigate whether or not CST administration directly into the hippocampus affects short- and long-term memory (STM and LTM, respectively) as well as the process of extinction, evaluated by a footshock passive avoidance test and additionally if CST affects cAMP production in hippocampal cells.