Fetal brain response to maternal inflammation requires microglia.

In utero infection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal brain infection, is associated with an increased risk of neuropsychiatric disorders in affected offspring. The cell types mediating the fetal brain response to maternal inflammation are largely unknown, hindering the development of novel treatment strategies. Here, we show that microglia, the resident phagocytes of the brain, highly express receptors for relevant pathogens and cytokines throughout embryonic development. Using a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant mice, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life. We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA. These findings demonstrate that microglia play a crucial durable role in the fetal response to maternal inflammation, and should be explored as potential therapeutic cell targets.

Making Ramón y Cajal proud: Development of cell identity and diversity in the cerebral cortex.

Since the beautiful images of Santiago Ramón y Cajal provided a first glimpse into the immense diversity and complexity of cell types found in the cerebral cortex, neuroscience has been challenged and inspired to understand how these diverse cells are generated and how they interact with each other to orchestrate the development of this remarkable tissue. Some fundamental questions drive the field's quest to understand cortical development: what are the mechanistic principles that govern the emergence of neuronal diversity? How do extrinsic and intrinsic signals integrate with physical forces and activity to shape cell identity? How do the diverse populations of neurons and glia influence each other during development to guarantee proper integration and function? The advent of powerful new technologies to profile and perturb cortical development at unprecedented resolution and across a variety of modalities has offered a new opportunity to integrate past knowledge with brand new data. Here, we review some of this progress using cortical excitatory projection neurons as a system to draw out general principles of cell diversification and the role of cell-cell interactions during cortical development.

A Light Touch on Sociability.

Autism spectrum disorder (ASD) is prevalent, complex, and heterogeneous, and currently there is no cure. Identifying shared mechanisms across the ASD spectrum is of utmost importance for therapeutic intervention. Orefice et al. show that tackling the GABAA receptor pathway in the peripheral somatosensory system in various ASD mouse models rescues core ASD-like phenotypes.

The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour.

Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neuropsychiatric disorders. Cyfip1-deficient mice also present decreased myelination in the callosal axons, altered presynaptic function, and impaired bilateral connectivity. Finally, Cyfip1 deficiency leads to abnormalities in motor coordination, sensorimotor gating and sensory perception, which are also known neuropsychiatric disorder-related symptoms. These results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders.

Maintenance mechanisms of circuit-integrated axons.

Adult, circuit-integrated neurons must be maintained and supported for the life span of their host. The attenuation of either maintenance or plasticity leads to impaired circuit function and ultimately to neurodegenerative disorders. Over the last few years, significant discoveries of molecular mechanisms were made that mediate the formation and maintenance of axons. Here, we highlight intrinsic and extrinsic mechanisms that ensure the health and survival of axons. We also briefly discuss examples of mutations associated with impaired axonal maintenance identified in specific neurological conditions. A better understanding of these mechanisms will therefore help to define targets for therapeutic interventions.

Hippocampal Dendritic Spines Are Segregated Depending on Their Actin Polymerization.

Dendritic spines are mushroom-shaped protrusions of the postsynaptic membrane. Spines receive the majority of glutamatergic synaptic inputs. Their morphology, dynamics, and density have been related to synaptic plasticity and learning. The main determinant of spine shape is filamentous actin. Using FRAP, we have reexamined the actin dynamics of individual spines from pyramidal hippocampal neurons, both in cultures and in hippocampal organotypic slices. Our results indicate that, in cultures, the actin mobile fraction is independently regulated at the individual spine level, and mobile fraction values do not correlate with either age or distance from the soma. The most significant factor regulating actin mobile fraction was the presence of astrocytes in the culture substrate. Spines from neurons growing in the virtual absence of astrocytes have a more stable actin cytoskeleton, while spines from neurons growing in close contact with astrocytes show a more dynamic cytoskeleton. According to their recovery time, spines were distributed into two populations with slower and faster recovery times, while spines from slice cultures were grouped into one population. Finally, employing fast lineal acquisition protocols, we confirmed the existence of loci with high polymerization rates within the spine.

FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.

Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity.

Neurotrophin receptor p75(NTR) mediates Huntington's disease-associated synaptic and memory dysfunction.

Learning and memory deficits are early clinical manifestations of Huntington's disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75(NTR) negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75(NTR) function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75(NTR) are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75(NTR) levels in HD mutant mice heterozygous for p75(NTR) prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75(NTR) in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75(NTR) in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75(NTR) mediates synaptic, learning, and memory dysfunction in HD.

Learning improvement after PI3K activation correlates with de novo formation of functional small spines.

PI3K activation promotes the formation of synaptic contacts and dendritic spines, morphological features of glutamatergic synapses that are commonly known to be related to learning processes. In this report, we show that in vivo administration of a peptide that activates the PI3K signaling pathway increases spine density in the rat hippocampus and enhances the animals' cognitive abilities, while in vivo electrophysiological recordings show that PI3K activation results in synaptic enhancement of Schaffer and stratum lacunosum moleculare inputs. Morphological characterization of the spines reveals that subjecting the animals to contextual fear-conditioning training per se promotes the formation of large spines, while PI3K activation reverts this effect and favors a general change toward small head areas. Studies using hippocampal neuronal cultures show that the PI3K spinogenic process is NMDA-dependent and activity-independent. In culture, PI3K activation was followed by mRNA upregulation of glutamate receptor subunits and of the immediate-early gene Arc. Time-lapse studies confirmed the ability of PI3K to induce the formation of small spines. Finally, we demonstrate that the spinogenic effect of PI3K can be induced in the presence of neurodegeneration, such as in the Tg2576 Alzheimer's mouse model. These findings highlight that the PI3K pathway is an important regulator of neuronal connectivity and stress the relationship between spine size and learning processes.