Assembly of the C1d projection of the central microtubule pair apparatus in mammalian motile cilia requires the ciliary protein CFAP54. Loss of the C1d projection in mice lacking CFAP54 impairs ciliary motility and cilia-driven fluid flow and results in a primary ciliary dyskinesia phenotype.

The juvenile onset form of neuronal ceroid lipofuscinoses (JNCL) is a recessively inherited lysosomal storage disorder characterized by progressive neurodegeneration. JNCL results from mutations in the CLN3 gene that encodes a lysosomal membrane protein with unknown function. Utilizing a Cln3-knock-out mouse model of JNCL that was created on the 129S6/SvEv genetic background, we have previously demonstrated that CLN3-deficient cerebellar granule cells (CGCs) have a selectively increased sensitivity to AMPA-type glutamate receptor-mediated toxicity. Our recent findings that CGCs from 129S6/SvEv and C57BL/6J wild type (WT) mice have significant differences in glutamate receptor expression and in excitotoxic vulnerability indicated that the genetic background possibly have a strong influence on how glutamate receptor function is dysregulated in CLN3-deficient neurons. Indeed, here we show that in the Cln3Δex7/8-knock-in mouse model, that is on the C57BL/6J genetic background, mimics the most frequent mutation observed in JNCL patients and considered a null mutant, the sensitivity of CGCs to both AMPA- and NMDA-type glutamate receptor overactivations is altered. Cultured wild type and Cln3Δex7/8 CGCs were equally sensitive to AMPA toxicity after 2 or 3 weeks in vitro, whereas the subunit-selective AMPA receptor agonist, CPW-399, induced significantly more cell death in mature, 3-week-old Cln3Δex7/8 cultures. NMDA receptor-mediated toxicity changed during in vitro development: Cln3Δex7/8 CGCs were less sensitive to high concentration of NMDA after 2 weeks in culture but became more vulnerable than their WT counterparts after 3 weeks in vitro. Abnormally altered glutamate receptor function in the cerebellum may result in motor deficits, and we confirmed that 7-week-old Cln3Δex7/8 mice, similarly to Cln3-knock-out mice, have a motor coordination deficit as measured by an accelerating rotarod. Our results demonstrate altered glutamate receptor function in Cln3Δex7/8 neurons and suggest that both AMPA and NMDA receptors are potential therapeutic targets in JNCL.

Hydrocephalus is caused by the accumulation of cerebrospinal fluid in the cerebral ventricular system which results in an enlargement of the cranium due to increased intraventricular pressure. The increase in pressure within the brain typically results in sloughing of ciliated ependymal cells, loss of cortical grey matter, and increased gliosis. Congenital hydrocephalus is associated with several syndromes including primary ciliary dyskinesia (PCD), a rare, genetically heterogeneous, pediatric syndrome that results from defects in motile cilia and flagella. We have examined the morphological and physiological defects in the brains of two mouse models of PCD, nm1054 and bgh, which have mutations in Pcdp1 (also known as Cfap221) and Spef2, respectively. Histopathological and immunohistochemical analyses of mice with these mutations on the C57BL/6J and 129S6/SvEvTac genetic backgrounds demonstrate strain-dependent morphological brain damage. Alterations in astrocytosis, microglial activation, myelination, and the neuronal population were identified and are generally more severe on the C57BL/6J background. Analysis of ependymal ciliary clearance ex vivo and cerebrospinal fluid flow in vivo demonstrate a physiological defect in nm1054 and bgh mice on both genetic backgrounds, indicating that abnormal cilia-driven flow is not the sole determinant of the severity of hydrocephalus in these models. These results suggest that genetic modifiers play an important role in susceptibility to severe PCD-associated hydrocephalus.

Alterations in glutamatergic synapse function have been implicated in the pathogenesis of many different neurological disorders including ischemia, epilepsy, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. While studying glutamate receptor function in juvenile Batten disease on the C57BL/6J and 129S6/SvEv mouse backgrounds, we noticed differences unlikely to be due to mutation difference alone. We report here that primary cerebellar granule cell cultures from C57BL/6J mice are more sensitive to NMDA-mediated cell death. Moreover, sensitivity to AMPA-mediated excitotoxicity is more variable and is dependent upon the treatment conditions and age of the cultures. Glutamate receptor surface expression levels examined in vitro by in situ ELISA and in vivo by Western blot in surface cross-linked cerebellar samples indicated that these differences in sensitivity are likely due to strain-dependent differences in cell surface receptor expression levels. We propose that differences in glutamate receptor expression and in excitotoxic vulnerability should be taken into consideration in the context of characterizing disease models on the C57BL/6J and 129S6/SvEv mouse backgrounds.