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Progressive neuron loss in the thalamocortical system of Cln5 deficient mice:
evidence for distinct effects in Finnish variant late infantile NCL
C von Schantz1, SN Hansen3, CC Pontikis3, C Kielar3, NA Alexander3, O Kopra2, A
Jalanko1, and JD Cooper3
1
National Public Health Institute, Department of Medical Genetics and Molecular Medicine,
Biomedicum Helsinki, Finland
2
University of Helsinki, Neuroscience Center, Helsinki, Finland
3
Pediatric Storage Disorders Laboratory, Department of Neuroscience and Centre for The Cellular
Basis of Behaviour, Institute of Psychiatry, King’s College London, London, SE5 9NU, UK
Finnish variant LINCL (vLINCLFin) is the result of mutations in the CLN5 gene. To investigate the
pathogenic mechanisms that operate in vLINCLFin we have generated Cln5 null mutant mice
(Cln5-/-). These Cln5-/- mice reproduce the human disease phenotype, with a relatively late onset
and slowly progressing neurological disorder. To gain a detailed series of progressive pathological
landmarks in the Cln5 deficient CNS, we have now undertaken a stereological analysis of Cln5-/mice at different stages of disease progression. Unbiased Cavalieri estimates of regional volume
revealed a significant atrophy of the cortex, hippocampus, striatum and thalamus in Cln5-/- mice,
that was only apparent after 12 months of age. Cortical thickness measurements revealed a late
onset, widespread and generalized thinning of the cortex. 12 month old Cln5-/- mice exhibited
pronounced glial responses within individual thalamic nuclei and across the entire cortical mantle,
as confirmed by Western blotting. Astrocytosis was already evident at a very low level at one
month of age, with microglial activation delayed for several months. To explore the relationship
between these reactive changes and the onset of neuronal loss in the thalamocortical system we
undertook optical fractionator counts of the number of thalamic relay neurons and cortical neuron
populations. As in mouse models of other forms of NCL, the thalamocortical system of Cln5
deficient mice displayed progressive neuron loss that became more pronounced with increased age.
However, in marked contrast to CtsD, Ppt1, and Cln3 deficient mice, neuron loss in
Cln5-/- mice was first evident in the cortex and was only subsequently detected in thalamic relay
neurons at 12 months of age. Taken together these data provide evidence for a distinct sequence of
pathological events in the Cln5 deficient CNS and it will be important to determine their molecular
and mechanistic basis.