Age-dependent loss of parvalbumin-expressing hippocampal interneurons in mice deficient in CHL1, a mental retardation and schizophrenia susceptibility gene

In humans, deletions/mutations in the CHL1/CALL gene are associated with mental retardation and schizophrenia. Juvenile CHL1-deficient (CHL1(-/-)) mice have been shown to display abnormally high numbers of parvalbumin-expressing (PV+) hippocampal interneurons and, as adults, display behavioral traits observed in neuropsychiatric disorders. Here, we addressed the question whether inhibitory interneurons and synaptic plasticity in the CHL1(-/-) mouse are affected during brain maturation and in adulthood. We found that hippocampal, but not neocortical, PV+ interneurons were reduced with age in CHL1(-/-) mice, from a surplus of +27% at 1month to a deficit of -20% in adulthood compared with wild-type littermates. This loss occurred during brain maturation, correlating with microgliosis and enhanced interleukin-6 expression. In parallel with the loss of PV+ interneurons, the inhibitory input to adult CA1 pyramidal cells was reduced and a deficit in short- and long-term potentiation developed at CA3-CA1 excitatory synapses between 2 and 9months of age in CHL1(-/-) mice. This deficit could be abrogated by a GABA(A) receptor agonist. We propose that region-specific aberrant GABAergic synaptic connectivity resulting from the mutation and a subsequently enhanced synaptic elimination during brain maturation lead to microgliosis, increase in pro-inflammatory cytokine levels, loss of interneurons, and impaired synaptic plasticity.