Extracerebellar role for Cerebellin1: Modulation of dendritic spine density and synapses in striatal medium spiny neurons

Abstract

Keywords Cbln1; dopamine; intralaminar; parafascicular nucleus; thalamostriatalCerebellin1 (Cbln1) is a secreted glycoprotein that was originally isolated from the cerebellum and subsequently found to regulate synaptic development and stability. Cbln1 has a heterogeneous distribution in brain, but the only site in which it has been shown to have central effects is the cerebellar cortex, where loss of Cbln1 causes a reduction in granule cell-Purkinje cell synapses. Neurons of the thalamic parafascicular nucleus (PF), which provide glutamatergic projections to the striatum, also express high levels of Cbln1. We first examined Cbln1 in thalamostriatal neurons and then determined if cbln1 knockout mice exhibit structural deficits in striatal neurons. Virtually all PF neurons expressed Cbln1-immunoreactivity (-ir). In contrast, only rare Cbln1-ir neurons are present in the central medial complex, the other thalamic region that projects heavily to the dorsal striatum. In the striatum Cbln1-ir processes are apposed to medium spiny neuron (MSN) dendrites; ultrastructural studies revealed that Cbln1-ir axon terminals form axodendritic synapses with MSNs. Tract tracing studies found that all PF cells retrogradely-labeled from the striatum express Cbln1-ir. We then examined the dendritic structure of Golgi-impregnated MSNs in adult cbln1 knockout mice. MSN dendritic spine density was markedly increased in cbln1 −/− mice relative to wildtype littermates, but total dendritic length was unchanged. Ultrastructural examination revealed an increase in the density of MSN axospinous synapses in cbln1 −/− mice, with no change in PSD length. Thus, Cbln1 determines the dendritic structure of striatal MSNs, with effects distinct from those seen in the cerebellum. Precerebellin (Cbln1) was originally isolated as the precursor of a cerebellar peptide cerebellin (Slemmon et al., 1984) and was subsequently shown to define a subfamily (Cbln1-4) of the C1q/TNFα superfamily of proteins (Urade et al., 1991;Pang et al., 2000;Bao et al., 2005). Cbln1 is secreted as homo-and hetero-trimeric complexes from granule cells (Pang et al., 2000;Bao et al., 2005Bao et al., , 2006Wei et al., 2007), and is essential for maintaining the structure and function of parallel fiber-Purkinje cell (pf-PC) synapses (Hirai et al., 2005). Cbln1 null mutant mice have a decreased number of pf-PC synapses, with

Roles of Cbln1 in Non-Motor Functions of Mice

“…The dorsal hippocampus and RSG are thought to mediate retrieval/retention of context-dependent fear memory (Kim and Fanselow, 1992;Keene andBucci, 2008a, 2008b;Corcoran et al, 2011). The ventral hippocampus is thought to mainly mediate retention/retrieval of cue-dependent fear memory; however, it also affects contextual memory (Maren and Holt, 2004;Hunsaker and Kesner, 2008;Fanselow and Dong, 2010).…”

“…3 E, F ), suggesting that Cbln1 in the hippocampus is derived from excitatory input fibers (see the Discussion). Together, these results indicate that Cbln1 may function in extracerebellar brain regions, such as the hippocampus and RSG, which are reported to be involved in cue-and/or contextdependent fear conditioning (Kim and Fanselow, 1992;Maren and Holt, 2004;Hunsaker and Kesner, 2008;Keene andBucci, 2008a, 2008b;Fanselow and Dong, 2010;Corcoran et al, 2011).…”

“…Therefore, the discrepancy may be explained by the less severe functional impairment in the L7-gabra2 Ϫ / Ϫ and L7-Slc12a5 Ϫ / Ϫ cerebellum. Indeed, two of five ASD mouse models, L7-Cre;tsc1 ϩ/flox and Shank3 ϩ/ ⌬ C , in which disrupted genes were specifically expressed in the cerebellum, showed ASD-related behaviors such as impaired social behavior, repetitive behaviors, and ultrasonic vocalization (Kloth et al, 2015). Interestingly, delayed eye-blink conditioning, a form of associative sensory learning, was also perturbed in these mice.…”

“…Interestingly, delayed eye-blink conditioning, a form of associative sensory learning, was also perturbed in these mice. Cerebellar circuits play essential roles in determining the adaptive timing of conditioned responses by associating an air puff (US) with tone (Koekkoek et al, 2003) and other sensory modalities (Ohmae and Medina, 2015) during eyeblink conditioning. It is thus possible that the cerebellum, by communicating with the forebrain, may help to integrate US with sensory modalities in a time window during the acquisition phase of cued and contextual fear conditioning.…”

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…Only Cbln1 KO mice have been analyzed in detail, and exhibit a phenotype that is virtually identical to that of GluD2 KO mice (Hirai et al, 2005; Otsuka et al, 2016; Kusnoor et al, 2010; Ito-Ishida et al, 2008 and 2014). The fact that Nrxn1 and Nrxn3 are essential for survival (Missler et al, 2003; Aoto et al, 2015), but their binding partners cerebellins and GluD2 are not, may be due to the interactions of neurexins with many different postsynaptic partners, whereas Cbln1 and Cbln2 and GluD2 appear to only bind to each other and to neurexins, and thus only mediate part of the overall functions of neurexins.…”