Interhemispheric CA1 projections support spatial cognition and are affected in a mouse model of the 22q11.2 deletion syndrome.

Untangling the hippocampus connectivity is critical for understanding the mechanisms supporting learning and memory. However, the function of interhemispheric connections between hippocampal formations is still poorly understood. So far, two major hippocampal commissural projections have been characterized in rodents. Mossy cells from the hilus of the dentate gyrus project to the inner molecular layer of the contralateral dentate gyrus and CA3 and CA2 pyramidal neuron axonal collaterals to contralateral CA3, CA2 and CA1. In contrary, little is known about commissural projection from the CA1 region. Here, we show that CA1 pyramidal neurons from the dorsal hippocampus project to contralateral dorsal CA1 as well as dorsal subiculum. We further demonstrate that the interhemispheric projection from CA1 to dorsal subiculum supports spatial memory and spatial working memory in WT mice, two cognitive functions impaired in male mice from the Df16(A) +/- model of 22q11.2 deletion syndrome (22q11.2DS) associated with schizophrenia. Investigation of the CA1 interhemispheric projections in Df16(A) +/- mice revealed that these projections are disrupted with male mutants showing stronger anatomical defects compared to females. Overall, our results characterize a novel interhemispheric projection from dCA1 to dorsal subiculum and suggest that dysregulation of this projection may contribute to the cognitive deficits associated with the 22q11.2DS.

Early cortical GABAergic interneurons determine the projection patterns of L4 excitatory neurons.

During cerebral cortex development, excitatory pyramidal neurons (PNs) establish specific projection patterns while receiving inputs from GABAergic inhibitory interneurons (INs). Whether these inhibitory inputs can shape PNs' projection patterns is, however, unknown. While layer 4 (L4) PNs of the primary somatosensory (S1) cortex are all born as long-range callosal projection neurons (CPNs), most of them acquire local connectivity upon activity-dependent elimination of their interhemispheric axons during postnatal development. Here, we demonstrate that precise developmental regulation of inhibition is key for the retraction of S1L4 PNs' callosal projections. Ablation of somatostatin INs leads to premature inhibition from parvalbumin INs onto S1L4 PNs and prevents them from acquiring their barrel-restricted local connectivity pattern. As a result, adult S1L4 PNs retain interhemispheric projections responding to tactile stimuli, and the mice lose whisker-based texture discrimination. Overall, we show that temporally ordered IN activity during development is key to shaping local ipsilateral S1L4 PNs' projection pattern, which is required for fine somatosensory processing.

Development and plasticity of the corpus callosum.

The corpus callosum (CC) connects the cerebral hemispheres and is the major mammalian commissural tract. It facilitates bilateral sensory integration and higher cognitive functions, and is often affected in neurodevelopmental diseases. Here, we review the mechanisms that contribute to the development of CC circuits in animal models and humans. These species comparisons reveal several commonalities. First, there is an early period of massive axonal projection. Second, there is a postnatal temporal window, varying between species, in which early callosal projections are selectively refined. Third, sensory-derived activity influences axonal refinement. We also discuss how defects in CC formation can lead to mild or severe CC congenital malformations.

Author Correction: Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1.

The original version of this Article contained an error in the spelling of the author Álvaro Sebastián-Serrano, which was incorrectly given as Álvaro Sebastián Serrano. This has now been corrected in both the PDF and HTML versions of the Article.

Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1.

Excitotoxicity, a critical process in neurodegeneration, induces oxidative stress and neuronal death through mechanisms largely unknown. Since oxidative stress activates protein kinase D1 (PKD1) in tumor cells, we investigated the effect of excitotoxicity on neuronal PKD1 activity. Unexpectedly, we find that excitotoxicity provokes an early inactivation of PKD1 through a dephosphorylation-dependent mechanism mediated by protein phosphatase-1 (PP1) and dual specificity phosphatase-1 (DUSP1). This step turns off the IKK/NF-κB/SOD2 antioxidant pathway. Neuronal PKD1 inactivation by pharmacological inhibition or lentiviral silencing in vitro, or by genetic inactivation in neurons in vivo, strongly enhances excitotoxic neuronal death. In contrast, expression of an active dephosphorylation-resistant PKD1 mutant potentiates the IKK/NF-κB/SOD2 oxidative stress detoxification pathway and confers neuroprotection from in vitro and in vivo excitotoxicity. Our results indicate that PKD1 inactivation underlies excitotoxicity-induced neuronal death and suggest that PKD1 inactivation may be critical for the accumulation of oxidation-induced neuronal damage during aging and in neurodegenerative disorders.