Anxiety disorders are the most frequent mental disorders and are more prevalent in the female population. Up to date, an involvement of guanylate cyclase A and B in anxiety‐like behavior has been suggested. In this study, we showed an expression of guanylate cyclase C (GC‐C) in the amygdala which is regulated by feeding. Therefore, we further investigated sex differences of GC‐C effects on anxiety levels with special attention to female estrous cycle and feeding. The effects of estrous cycle and feeding were investigated by several behavior tests: elevated plus maze, home cage escape and novelty‐induced hypophagy. Possible changes in GC‐C expression in amygdala and hypothalamus during estrous cycle were established by qPCR. When GC‐C is activated (after a meal), the sex difference in all behavior tests used was abolished. As the expression of mRNA for GC‐C in the amygdala increases 2 hr after a meal only in female animals, the anxiety levels change after a meal again only in female animals. When the anxiety levels are investigated, it is very important to pay attention not only to estrous cycle in female animals but also when animals were fed compared to the time point of the experiments. Concluding from our results, the sex differences in the incidence of anxiety disorders in humans could be GC‐C dependent.

Aim To investigate the cyclic guanosine monophosphate (cGMP)/guanylate cyclase C (GC-C) -independent signaling pathway in astrocytes, which are a suitable model due to their lack of GC-C expression. Methods Patch clamp was performed and intracellular Ca 2+ concentrations and pH were measured in primary astrocyte cultures and brain slices of wild type (WT) and GC-C knockout (KO) mice. The function of GC-C-independent signaling pathway in the cerebellum was determined by behavior tests in uroguanylin (UGN) KO and GC-C KO mice. Results We showed for the first time that UGN changed intracellular Ca 2+ levels in different brain regions of the mouse. In addition to the midbrain and hypothalamus, GC-C was expressed in the cerebral and cerebellar cortex. The presence of two signaling pathways in the cerebellum (UGN hyperpolarized Purkinje cells via GC-C and increased intracellular Ca 2+ concentration in astrocytes) led to a different motoric function in GC-C KO and UGN KO mice, probably via different regulation of intracellular pH in astrocytes. Conclusion The UGN effects on astrocytes via a Ca 2+ -dependent signaling pathway could be involved in the modulation of neuronal activity.

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Stroke is one of the leading causes of mortality and disability worldwide. By affecting bradykinin function, activation of guanylate cyclase (GC)-A has been shown to have a neuroprotective effect after ischaemic stroke, whereas the same has not been confirmed for GC-B; therefore, we aimed to determine the possible role of GC-C and its agonist, uroguanylin (UGN), in the development of stroke. In this study, middle cerebral artery occlusion (MCAO) was performed on wild-type (WT), GC-C KO and UGN KO mice. MR images were acquired before and 24 h after MCAO. On brain slices 48 h after MCAO, the Ca 2+ response to UGN stimulation was recorded. Our results showed that the absence of GC-C in GC-C KO mice resulted in the development of smaller ischaemic lesions compared with WT littermates, which is an opposite effect compared with the effects of GC-A agonists on brain lesions. WT and UGN KO animals showed a stronger Ca 2+ response upon UGN stimulation in astrocytes of the peri-ischaemic cerebral cortex compared with the same cortical region of the unaffected contralateral hemisphere. This stronger activation was not observed in GC-C KO animals, which may be the reason for smaller lesion development in GC-C KO mice. The reason why GC-C might affect Ca 2+ signalling in peri-ischaemic astrocytes is that GC-C is expressed in these cells after MCAO, whereas under normoxic conditions, it is expressed mainly in cortical neurons. Stronger activation of the Ca 2+ -dependent signalling pathway could lead to the stronger activation of the Na + /H + exchanger, tissue acidification and neuronal death.

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