Secretin Facilitates GABA Transmission in the Cerebellum

Abstract

Secretin was the first hormone discovered in human history, and yet, its function as a neuropeptide has been overlooked in the past. The recent discovery of the potential use of secretin in treating autistic patients, together with the conflicting reports on its effectiveness, urges an in-depth investigation of this issue. We show here that in the rat cerebellar cortex, mRNAs encoding secretin are localized in the Purkinje cells, whereas those of its receptor are found in both Purkinje cells and GABAergic interneurons. Immunoreactivity for secretin is localized in the soma and dendrites of Purkinje cells. In addition, secretin facilitates evoked, spontaneous, and miniature IPSCs recorded from Purkinje cells. We propose that secretin is released from the somatodendritic region of Purkinje cells and serves as a retrograde messenger modulating GABAergic afferent activity.

The Knockout of Secretin in Cerebellar Purkinje Cells Impairs Mouse Motor Coordination and Motor Learning

“…This is the first time that SCT expression has been manipulated in specific cells and hence provides a more powerful model to investigate the exact function of SCT in specific cells. In WT mice, SCT was strongly expressed in the soma and dendrites of Purkinje cells (Figures 1b and d), consistent with results obtained from a previous rat cerebellum study (Yung et al, 2001). In Pur-Sct À / À mice, SCT was still expressed in the deep cerebellar nuclei, hippocampus, and hypothalamus (Figures 1f-i) as previously described (Ng et al, 2002), confirming the Purkinjespecific knockout of SCT.…”

“…Moreover, rotarod motor latencies for Sct À / À , Sctr À / À , and Pur-Sct À / À mice increased slightly after repeated trials (Figures 3c and d), illustrating motor learning deficits. The abnormal behavioral phenotypes that we discovered, combined with results from previous studies on the SCT-mediated potentiation of rat Purkinje cell IPSCs (Yung et al, 2001) and the specific knockout of SCT in Purkinje cells of the mouse model, strongly support the involvement of the SCT-SCTR axis in motor coordination and learning abilities through the modulation of Purkinje cell neural transmission.…”

“…Potential effects on two pathways, ie, neural transmission and/or neural development, may help to explain the motor coordination and learning deficits. For neural transmission, we have demonstrated that SCT can potentiate GABAergic IPSCs in basketPurkinje cell synaptic transmission from rats (Yung et al, 2001). The underlying mechanism has been suggested to be the suppression of potassium channel Kv1.2 trafficking in basket cell-Purkinje neuron synapses (Williams et al, 2012).…”

“…Previous studies have demonstrated that SCT can be endogenously released from rat cerebellar Purkinje cells following Ca 2 þ entry and functions as a retrograde neuropeptide to potentiate GABAergic inhibitory postsynaptic currents (IPSCs) from basket cells via specific binding to SCTR (Lee et al, 2005;Yung et al, 2001). One possible mechanism of this potentiation was suggested to be the suppression of potassium channel Kv1.2 trafficking in both basket cell axon terminals and Purkinje dendrites after SCT application (Williams et al, 2012).…”

Secretin induces neurite outgrowth of PC12 through cAMP-mitogen-activated protein kinase pathway

“…Secretin has also been determined to be expressed in distinct neuronal populations within the cerebellum and cerebral cortex (Couvineau et al, 1986;Yung et al, 2001). It has also been reported that VIP, which is structurally similar to secretin, exhibited neurite-promoting effects in ventral spinal cord cells (Iwasaki et al, 2001).…”