Enhanced homosynaptic LTD in cerebellar Purkinje cells of the dystrophic MDX mouse

Abstract

The purpose was to study homosynaptic long-term depression (LTD) at the parallel fiber-Purkinje cell synapse in the mdx mouse, a murine model of the human dystrophinopathy, Duchenne muscular dystrophy (DMD), in order to examine whether the absence of dystrophin affects the induction and extent of this form of synaptic plasticity. Sharp intracellular electrodes were used to record electrically evoked excitatory postsynaptic potentials (EPSPs) from identified Purkinje cells in cerebellar slices. The early phase of homosynaptic LTD, 7-16 min postinduction, was the same in mdx and wildtype Purkinje cells; however, the late phase of LTD, 35-44 min, was significantly enhanced in mdx Purkinje cells. We hypothesize that this enhancement of the late phase of homosynaptic LTD may be due to a disruption of Ca(2+) homeostasis associated with the absence of the protein dystrophin. These findings may explain some of the central nervous system deficiencies reported in DMD boys.

Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies

“…Current hypotheses consider that the brain alterations are most likely located at the cellular level, and there is now ample evidence that the Dp427-DGC modulates synapse function in brain structures expressing dystrophin. In Purkinje cells of cerebellum, mdx mice display reduced heterosynaptic long-term depression (LTD) of neurotransmission [120], whereas homosynaptic LTD is enhanced [121]. In the hippocampus of the mdx mouse, we found that NMDA receptor-dependent short- (STP) and long-term potentiation (LTP) as well as LTD are all abnormally enhanced in the CA1 dendritic layer [110, 112, 115].…”

Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes

“…These structures normally express dystrophin Dp427. Moreover, an impaired clustering of GABA A receptors has been characterized in mdx mice in central inhibitory synapses in hippocampus, amygdala and cerebellum -but not in the striatum - (Knuesel et al, 1999;Sekiguchi et al, 2009;Vaillend et al, 2010) and this has been associated with altered synaptic plasticity in these structures (Anderson, Morley, & Head, 2010;Dallérac et al, 2011;Sekiguchi et al, 2009;Vaillend et al, 2004). Altered GABAergic function in these regions could be a basis of the learning and memory deficits in mdx mice (Makkar, Zhang, & Cranney, 2010), since previous studies unveiled hippocampal-dependent ; for a review) and cerebellum-dependent deficits in this model (Grady et al, 2006), while our present results suggest a major involvement of the amygdala.…”

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy

“…Their results are consistent with other reports that showed a reduction in the number of GABA synapses on Purkinje cells (Kueh et al, 2011), aberrant GABA release and uptake in cerebellar synaptosomes (Pereira da Silva et al, 2018), and a reduction in postsynaptic long-term depression (LTD) in mdx Purkinje cells [although Sesay et al (1996) found no LTP changes in mdx urethane-anesthetized hippocampal cells, which could be related to the anesthetic effects of urethane (Hara and Harris, 2002)]. Interestingly, homosynaptic LTD at parallel fiber-Purkinje cell synapses is enhanced in mdx mutant mice (Anderson et al, 2010), but how altering these intrinsic membrane properties of Purkinje cells affects circuit function in the intact cerebellum in vivo remains largely unsolved.…”