Dual involvement of G-substrate in motor learning revealed by gene deletion

Abstract

In this study, we generated mice lacking the gene for G-substrate, a specific substrate for cGMP-dependent protein kinase uniquely located in cerebellar Purkinje cells, and explored their specific functional deficits. G-substrate-deficient Purkinje cells in slices obtained at postnatal weeks (PWs) 10 -15 maintained electrophysiological properties essentially similar to those from WT littermates. Conjunction of parallel fiber stimulation and depolarizing pulses induced long-term depression (LTD) normally. At younger ages, however, LTD attenuated temporarily at PW6 and recovered thereafter. In parallel with LTD, short-term (1 h) adaptation of optokinetic eye movement response (OKR) temporarily diminished at PW6. Young adult G-substrate knockout mice tested at PW12 exhibited no significant differences from their WT littermates in terms of brain structure, general behavior, locomotor behavior on a rotor rod or treadmill, eyeblink conditioning, dynamic characteristics of OKR, or short-term OKR adaptation. One unique change detected was a modest but significant attenuation in the long-term (5 days) adaptation of OKR. The present results support the concept that LTD is causal to short-term adaptation and reveal the dual functional involvement of G-substrate in neuronal mechanisms of the cerebellum for both short-term and long-term adaptation.cerebellum ͉ long-term depression ͉ optokinetic response ͉ Purkinje cell

Lipid signaling in cytosolic phospholipase A 2 α–cyclooxygenase-2 cascade mediates cerebellar long-term depression and motor learning

“…Whether LTD actually underlies motor learning is a matter of discussion. In a number of knockout mutants tested so far, the loss of LTD detected in slice conditions parallels a disturbance in motor learning (21), or, in a certain case, enhanced LTD parallels an enhanced motor learning (46). However, in a fragile-X mental retardation mouse model, enhanced LTD accompanies impaired motor learning (47).…”

“…1). Furthermore, to test the current hypothesis that LTD underlies motor learning, we examine whether the deficiency of cPLA 2 α or the i.p.administration of a COX-2 inhibitor affects the adaptation of optokinetic eye movement response (OKR) in awake mice (21). Part of the present findings have been reported preliminarily.…”

Motor Learning and the Cerebellum

“…By experimentally moving a subject's head while also moving the visual environment in the same or opposite direction (i.e., in or out of phase), this reflex will prove insufficient or exaggerated, until the new rules are integrated in the compensatory eye movements following a process of adaptation learning. Mechanical or genetic lesions of floccular Purkinje cells severely hamper adaptation of compensatory eye movements (Endo et al 2009;Gao et al 2012). Recordings of Purkinje cells in the flocculus of awake behaving mammals during a vestibulo-ocular reflex paradigm in the dark or light show simple spike modulation that correlates well with both maximum head velocity and maximum eye velocity (De Zeeuw et al 1995).…”

Role of Cerebellar Cortical Protein Synthesis in Transfer of Memory Trace of Cerebellum-Dependent Motor Learning

“…Floccular infusions of N G -monomethyl-L-arginine, which blocks LTD/long-term potentiation (LTP) of parallel fiberPurkinje cell (pf-PC) synapses, depress both the acquisition and transfer of the memory of HOKR adaptation in mice (Shutoh et al, 2006). In mice genetically devoid of the substrate for the cyclic GMP-dependent protein kinase, which is uniquely concentrated in Purkinje cells, the acquisition of memory of HOKR adaptation is normal, but the memory transfer is specifically attenuated (Endo et al, 2009). In mice in which feedforward inhibitory inputs to Purkinje cells are removed genetically, the transfer of memory trace of HVOR adaptation is specifically impaired (Wulff et al, 2009).…”