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

Abstract

Secretin (SCT) was first considered to be a gut hormone regulating gastrointestinal functions when discovered. Recently, however, central actions of SCT have drawn intense research interest and are supported by the broad distribution of SCT in specific neuronal populations and by in vivo physiological studies regarding its role in water homeostasis and food intake. The direct action of SCT on a central neuron was first discovered in cerebellar Purkinje cells in which SCT from cerebellar Purkinje cells was found to potentiate GABAergic inhibitory transmission from presynaptic basket cells. Because Purkinje neurons have a major role in motor coordination and learning functions, we hypothesize a behavioral modulatory function for SCT. In this study, we successfully generated a mouse model in which the SCT gene was deleted specifically in Purkinje cells. This mouse line was tested together with SCT knockout and SCT receptor knockout mice in a full battery of behavioral tasks. We found that the knockout of SCT in Purkinje neurons did not affect general motor ability or the anxiety level in open field tests. However, knockout mice did exhibit impairments in neuromuscular strength, motor coordination, and motor learning abilities, as shown by wire hanging, vertical climbing, and rotarod tests. In addition, SCT knockout in Purkinje cells possibly led to the delayed development of motor neurons, as supported by the later occurrence of key neural reflexes. In summary, our data suggest a role in motor coordination and motor learning for SCT expressed in cerebellar Purkinje cells.

Transient cerebellar alterations during development prior to obvious motor phenotype in a mouse model of spinocerebellar ataxia type 6

“…; Zhang et al . ). For the righting reflex assay, each mouse was placed on its back and the time it took the mouse to right itself was measured (Yu et al .…”

“…; Zhang et al . ). For the negative geotaxis assay, each mouse was placed on a 45 deg wooden inclined plane with its body pointed towards the base of the platform (Mocholi et al .…”

Cerebellar secretin modulates eyeblink classical conditioning

“…This finding compliments our previous finding that secretin facilitated EBC when infused into lobulus simplex of cerebellar cortex prior to acquisition sessions 1 -3 (Williams et al 2012). Since secretin is endogenously expressed in PCs in cerebellar cortex (Yung et al 2001;Köves et al 2002;Zhang et al 2014), is released when PCs are Figure 3. Experiment 2: mean + SEM percentage of eyeblink CRs as a function of session for adaptation, acquisition and extinction.…”

“…Other research has shown that secretin is expressed in the somatodendritic region of PCs (Yung et al 2001) and its G S -protein coupled receptor is expressed in PCs and basket cells (BCs) (Yung et al 2001;Köves et al 2002;Zhang et al 2014). Secretin release can be induced by depolarization of cerebellar tissue with KCl and this secretin release is inhibited by an L-type or a P/Q-type calcium channel blocker (Lee et al 2005).…”

“…Secretin increases inhibitory postsynaptic currents (IPSCs) recorded from PCs (Yung et al 2001;Lee et al 2005). Recently, it has been shown that Pur-Sct 2/2 mice, in which the secretin coding region is selectively deleted from PCs, are impaired in rota-rod learning (Zhang et al 2014). All of these data are consistent with our working model in which secretin, released from PCs depolarized by US input, promotes EBC by inhibiting PCs, which reduces inhibition on the IPN.…”