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BackgroundPlatelet-activating factor acetylhydrolase 1B1 (LIS1), a critical mediator of neuronal migration in developing brain, is expressed throughout life. However, relatively little is known about LIS1 function in the mature brain. We previously demonstrated that LIS1 involvement in the formation and turnover of synaptic protrusions and synapses of young brain after neuronal migration is complete. Here we examine the requirement for LIS1 to maintain hippocampal circuit function in adulthood.MethodsEffects of conditional Lis1 inactivation in excitatory pyramidal neurons, starting in juvenile mouse brain, were probed using high-resolution approaches combining mouse genetics, designer receptor exclusively activated by designer drug technology to specifically manipulate CA1 pyramidal neuron excitatory activity, electrophysiology, hippocampus-selective behavioral testing, and magnetic resonance imaging tractography to examine the connectivity of LIS1-deficient neurons.ResultsWe found progressive excitatory and inhibitory postsynaptic dysfunction as soon as 10 days after conditional inactivation of Lis1 targeting CA1 pyramidal neurons. Surprisingly, by postnatal day 60 it also caused CA1 histological disorganization, with a selective decline in parvalbumin-expressing interneurons and further reduction in inhibitory neurotransmission. Accompanying these changes were behavioral and cognitive deficits that could be rescued by either designer receptor exclusively activated by designer drug-directed specific increases in CA1 excitatory transmission or pharmacological enhancement of gamma-aminobutyric acid transmission. Lagging behind electrophysiological changes was a progressive, selective decline in neural connectivity, affecting hippocampal efferent pathways documented by magnetic resonance imaging tractography.ConclusionsLIS1 supports synaptic function and plasticity of mature CA1 neurons. Postjuvenile loss of LIS1 disrupts the structure and cellular composition of the hippocampus, its connectivity with other brain regions, and cognition dependent on hippocampal circuits.

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.