To investigate the function of the alpha calcium-calmodulin-dependent kinase II (alphaCaMKII) inhibitory autophosphorylation at threonines 305 and/or 306, we generated knockin mice that express alphaCaMKII that cannot undergo inhibitory phosphorylation. In addition, we generated mice that express the inhibited form of alphaCaMKII, which resembles the persistently phosphorylated kinase at these sites. Our data demonstrate that blocking inhibitory phosphorylation increases CaMKII in the postsynaptic density (PSD), lowers the threshold for hippocampal long-term potentiation (LTP), and results in hippocampal-dependent learning that seems more rigid and less fine-tuned. Mimicking inhibitory phosphorylation dramatically decreased the association of CaMKII with the PSD and blocked both LTP and learning. These data demonstrate that inhibitory phosphorylation has a critical role in plasticity and learning.

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain1,2. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins3–5. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain6–9.

Autosomal recessive primary microcephaly (MCPH) is characterised by a significant reduction in prenatal human brain growth, without alteration of cerebral architecture. The genetic aetiology of MCPH is bi-allelic mutations in genes coding for a subset of centrosomal proteins1-10. While at least three of these proteins have been implicated in centrosome duplication11, the nature of centrosome dysfunction that underlies the neurodevelopmental defect in MCPH is unclear. Here we report a homozygous MCPH-causing mutation in the human CEP63 gene. CEP63 forms a complex with another MCPH protein, CEP152, a conserved centrosome duplication factor12-15. Together, they are essential for maintaining normal centrosome numbers in cells. Using super-resolution microscopy we find that CEP63 and CEP152 co-localise in a discrete ring around the proximal end of the parental centriole, a pattern specifically disrupted in CEP63-deficient patient-derived cells. This work suggests that the CEP152-CEP63 ring-like structure ensures normal neurodevelopment and its impairment particularly affects human cerebral cortex growth.

We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

Animals depend on a large variety of rewards but their brains have a limited dynamic coding range. When rewards are uncertain, neuronal coding needs to cover a wide range of possible rewards. However, when reward is likely to occur within a specific range, focusing the sensitivity on the predicted range would optimize the discrimination of small reward differences. One way to overcome the trade-off between wide coverage and optimal discrimination is to adapt reward sensitivity dynamically to the available rewards. We investigated how changes in reward distribution influenced the coding of reward in the orbitofrontal cortex. Animals performed an oculomotor task in which a fixation cue predicted the SD of the probability distribution of juice volumes, while the expected mean volume was kept constant. A subsequent cue specified the exact juice volume obtained for a correct saccade response. Population responses of orbitofrontal neurons that reflected the predicted juice volume showed adaptation to the reward distribution. Statistical tests on individual responses revealed that a quarter of value-coding neurons shifted the reward sensitivity slope significantly between two reward distributions, whereas the remaining neurons showed insignificant change or lack of adaptation. Adaptations became more prominent when reward distributions changed less frequently, indicating time constraints for assessing reward distributions and adjusting neuronal sensitivity. The observed neuronal adaptation would optimize discrimination and contribute to the efficient coding of a large variety of potential rewards by neurons with limited dynamic range.

BackgroundNerve growth factor β (NGFβ) and tyrosine kinase receptor type A (TRKA) are a well studied neurotrophin/receptor duo involved in neuronal survival and differentiation. The only previously reported hereditary sensory neuropathy caused by an NGF mutation, c.661C>T (HSAN5), and the pathology caused by biallelic mutations in the TRKA gene (NTRK1) (HSAN4), share only some clinical features. A consanguineous Arab family, where five of the six children were completely unable to perceive pain, were mentally retarded, did not sweat, could not discriminate temperature, and had a chronic immunodeficiency, is reported here. The condition is linked to a new homozygous mutation in the NGF gene, c.[680C>A]+[681_682delGG].MethodsGenetic linkage and standard sequencing techniques were used to identify the causative gene. Using wild-type or mutant over-expression constructs transfected into PC12 and COS-7 cells, the cellular and molecular consequences of the mutations were investigated.ResultsThe mutant gene produced a precursor protein V232fs that was unable to differentiate PC12 cells. V232fs was not secreted from cells as mature NGFβ.ConclusionsBoth the clinical and cellular data suggest that the c.[680C>A]+[681_682delGG] NGF mutation is a functional null. The HSAN5 phenotype is extended to encompass HSAN4-like characteristics. It is concluded that the HSAN4 and HSAN5 phenotypes are parts of a phenotypic spectrum caused by changes in the NGF/TRKA signalling pathway.

(1) Background: We proposed to review worldwide estimates of cognitive impairment prevalence and incidence in adults older than 50 years of age living in the community. (2) Methods: Systematic searches were performed in January 2019 using MEDLINE/PubMed. Articles were selected if they referred to cognitive impairment, prevalence, incidence, elders, and population or community-based studies. Analysis, aggregated by different methodologic features, was performed. (3) Results: Prevalence (80 studies) ranged between 5.1% and 41% with a median of 19.0% (25th percentile = 12.0%; 75th percentile = 24.90%). Incidence (11 studies) ranged from 22 to 76.8 per 1000 person-years with a median of 53.97 per 1000 person-years (25th percentile = 39.0; 75th percentile = 68.19). No statistically significant effects were found except for inclusion age. (4) Conclusion: We propose that the homogenization and clarification of the definition of what constitutes cognitive impairment are essential to refine the epidemiological understanding of this entity. The results of this review reinforce the importance of adherence to standardized cut-off scores for cognitive tests to promote study comparability.