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1.
Exp Neurol ; 323: 113095, 2020 01.
Article in English | MEDLINE | ID: mdl-31712124

ABSTRACT

Currently, molecular, electrophysiological and structural studies delineate several neural subtypes in the hippocampus. However, the precise developmental mechanisms that lead to this diversity are still unknown. Here we show that alterations in a concrete hippocampal neuronal subpopulation during development specifically affect hippocampal-dependent spatial memory. We observed that the genetic deletion of the transcription factor Helios in mice, which is specifically expressed in developing hippocampal calbindin-positive CA1 pyramidal neurons (CB-CA1-PNs), induces adult alterations affecting spatial memory. In the same mice, CA3-CA1 synaptic plasticity and spine density and morphology in adult CB-CA1-PNs were severely compromised. RNAseq experiments in developing hippocampus identified an aberrant increase on the Visinin-like protein 1 (VSNL1) expression in the hippocampi devoid of Helios. This aberrant increase on VSNL1 levels was localized in the CB-CA1-PNs. Normalization of VSNL1 levels in CB-CA1-PNs devoid of Helios rescued their spine loss in vitro. Our study identifies a novel and specific developmental molecular pathway involved in the maturation and function of a CA1 pyramidal neuronal subtype.


Subject(s)
DNA-Binding Proteins/metabolism , Neurocalcin/metabolism , Neurogenesis/physiology , Pyramidal Cells/physiology , Spatial Memory/physiology , Transcription Factors/metabolism , Animals , CA1 Region, Hippocampal/growth & development , CA1 Region, Hippocampal/physiology , Dendritic Spines/metabolism , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Neuronal Plasticity/physiology , Pyramidal Cells/cytology
2.
Neuron ; 100(1): 201-215.e9, 2018 10 10.
Article in English | MEDLINE | ID: mdl-30290982

ABSTRACT

Pyramidal neuron dendrites integrate synaptic input from multiple partners. Different inputs converging on the same dendrite have distinct structural and functional features, but the molecular mechanisms organizing input-specific properties are poorly understood. We identify the orphan receptor GPR158 as a binding partner for the heparan sulfate proteoglycan (HSPG) glypican 4 (GPC4). GPC4 is enriched on hippocampal granule cell axons (mossy fibers), whereas postsynaptic GPR158 is restricted to the proximal segment of CA3 apical dendrites receiving mossy fiber input. GPR158-induced presynaptic differentiation in contacting axons requires cell-surface GPC4 and the co-receptor LAR. Loss of GPR158 increases mossy fiber synapse density but disrupts bouton morphology, impairs ultrastructural organization of active zone and postsynaptic density, and reduces synaptic strength of this connection, while adjacent inputs on the same dendrite are unaffected. Our work identifies an input-specific HSPG-GPR158 interaction that selectively organizes synaptic architecture and function of developing mossy fiber-CA3 synapses in the hippocampus.


Subject(s)
CA3 Region, Hippocampal/metabolism , Heparan Sulfate Proteoglycans/metabolism , Mossy Fibers, Hippocampal/metabolism , Receptors, G-Protein-Coupled/metabolism , Synapses/metabolism , Animals , CA3 Region, Hippocampal/embryology , HEK293 Cells , Humans , Mice , Mossy Fibers, Hippocampal/embryology , Neurogenesis/physiology , Pyramidal Cells/metabolism , Rats , Rats, Long-Evans , Synaptic Transmission/physiology
3.
J Alzheimers Dis ; 42(4): 1357-82, 2014.
Article in English | MEDLINE | ID: mdl-25024348

ABSTRACT

BACKGROUND: Although genome-wide association studies have shown that genetic factors increase the risk of suffering late-onset, sporadic Alzheimer's disease (SAD), the molecular mechanisms responsible remain largely unknown. OBJECTIVE: The aim of the study was to investigate the presence of somatic, brain-specific single nucleotide variations (SNV) in the hippocampus of SAD samples. METHODS: By using bioinformatic tools, we compared whole exome sequences in paired blood and hippocampal genomic DNAs from 17 SAD patients and from 2 controls and 2 vascular dementia patients. RESULTS: We found a remarkable number of SNVs in SAD brains (~575 per patient) that were not detected in blood. Loci with hippocampus-specific (hs)-SNVs were common to several patients, with 38 genes being present in 6 or more patients out of the 17. While some of these SNVs were in genes previously related to SAD (e.g., CSMD1, LRP2), most hs-SNVs occurred in loci previously unrelated to SAD. The most frequent genes with hs-SNVs were associated with neurotransmission, DNA metabolism, neuronal transport, and muscular function. Interestingly, 19 recurrent hs-SNVs were common to 3 SAD patients. Repetitive loci or hs-SNVs were underrepresented in the hippocampus of control or vascular dementia donors, or in the cerebellum of SAD patients. CONCLUSION: Our data suggest that adult blood and brain have different DNA genomic variations, and that somatic genetic mosaicism and brain-specific genome reshaping may contribute to SAD pathogenesis and cognitive differences between individuals.


Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Hippocampus/metabolism , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Cerebellum/metabolism , Dementia, Vascular/genetics , Dementia, Vascular/metabolism , Exome , Female , Humans , Male , Middle Aged
4.
Cereb Cortex ; 24(8): 2093-107, 2014 Aug.
Article in English | MEDLINE | ID: mdl-23479403

ABSTRACT

We studied the role of γ-aminobutyric acid (GABA)ergic septohippocampal projections in medial septum (MS) self-stimulation of behaving mice. Self-stimulation was evoked in wild-type (WT) mice using instrumental conditioning procedures and in J20 mutant mice, a type of mouse with a significant deficit in GABAergic septohippocampal projections. J20 mice showed a significant modification in hippocampal activities, including a different response for input/output curves and the paired-pulse test, a larger long-term potentiation (LTP), and a delayed acquisition and lower performance in the MS self-stimulation task. LTP evoked at the CA3-CA1 synapse further decreased self-stimulation performance in J20, but not in WT, mice. MS self-stimulation evoked a decrease in the amplitude of field excitatory postsynaptic potentials (fEPSPs) at the CA3-CA1 synapse in WT, but not in J20, mice. This self-stimulation-dependent decrease in the amplitude of fEPSPs was also observed in the presence of another positive reinforcer (food collected during an operant task) and was canceled by the local administration of an antibody-inhibiting glutamate decarboxylase 65 (GAD65). LTP evoked in the GAD65Ab-treated group was also larger than in controls. The hippocampus has a different susceptibility to septal GABAergic inputs depending on ongoing cognitive processes, and the GABAergic septohippocampal pathway is involved in consummatory processes related to operant rewards.


Subject(s)
Conditioning, Operant/physiology , GABAergic Neurons/physiology , Hippocampus/physiology , Septal Nuclei/physiology , Amyloid beta-Protein Precursor/genetics , Animals , Excitatory Postsynaptic Potentials/physiology , Glutamate Decarboxylase/metabolism , Humans , Long-Term Potentiation/physiology , Male , Mice, Inbred C57BL , Mice, Transgenic , Reward , Self Stimulation/physiology , Synapses/physiology , gamma-Aminobutyric Acid/metabolism
5.
FASEB J ; 26(11): 4458-67, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22835830

ABSTRACT

Patients with Alzheimer's disease (AD) display altered functioning of cortical networks, including altered patterns of synchronous activity and a serious deficit in cholinergic septohippocampal (SH) innervation. However, the mechanisms underlying these alterations and the implication of the GABAergic SH component in AD are largely unknown. In addition, the GABAergic septohippocampal pathway (SHP) is believed to regulate synchronous hippocampal activity by controlling the activity of interneurons. Here we show, using well-characterized pathway tracing experiments, that innervation of the GABAergic SHP decreases during normal aging. Furthermore, in an AD mouse model (hAPP(Sw,Ind); J20 mice), the GABAergic SHP shows a dramatic and early onset of this decrease in 8-mo-old mice. This decline is not caused by neuronal loss, but by the reduced number and complexity of GABAergic SH axon terminals. Finally, we demonstrate that hippocampal θ and γ rhythm power spectra are markedly diminished in 8-mo-old behaving mice expressing mutated hAPP. In addition to the well-known loss of cholinergic input to the hippocampus in AD, these data suggest that the altered patterns of synchronous activity seen in patients with AD could be caused by the loss of GABAergic SH axons, which modulate hippocampal network activities.


Subject(s)
Aging , Alzheimer Disease/metabolism , GABAergic Neurons/physiology , Hippocampus/physiology , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Disease Models, Animal , Hippocampus/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Neurologic Mutants , Mice, Transgenic , Septal Nuclei/cytology , Theta Rhythm/physiology
6.
Eur J Neurosci ; 34(12): 1923-33, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22092651

ABSTRACT

The septohippocampal (SH) pathway comprises cholinergic and GABAergic fibers. Whereas the former establish synaptic contacts with all types of hippocampal neurons, the latter form complex baskets specifically on interneurons. The GABAergic SH function is associated with the control of hippocampal synchronous networks. Little is known about the mechanisms involved in the formation of the GABAergic SH pathway. Semaphorin (Sema) 3C is expressed in most hippocampal interneurons targeted by these axons. To ascertain whether Sema 3C influences the formation of the SH pathway, we analyzed the development of this connection in Sema 3C-deficient mice. As these animals die at birth, we developed an in vitro organotypic co-culture model reproducing the postnatal development of the SH pathway. In these SH co-cultures, the GABAergic SH pathway developed with target specificity similar to that present in vivo. SH axons formed incipient baskets on several types of hippocampal interneurons at 7 days in vitro, which increased their complexity by 18-25 days in vitro. These SH fibers formed symmetric synaptic contacts on GABAergic interneurons. This synaptic specificity was not influenced by the absence of entorhinal afferents. Finally, the absence of Sema 3C in target neurons or its blockage by neuropilin-1 and -2 ectodomains in slice co-cultures did not lead to major changes in either the target specificity of the GABAergic SH pathway or its density of innervation. We conclude that the formation and synaptic specificity of the GABAergic SH pathway relies on robust molecular mechanisms, independent of Sema 3C, that are retained in our in vitro co-culture model.


Subject(s)
GABAergic Neurons/physiology , Hippocampus/anatomy & histology , Neural Pathways/physiology , Semaphorins/metabolism , Septum of Brain/anatomy & histology , Animals , Axons/physiology , Axons/ultrastructure , Cells, Cultured , Cholinergic Neurons/cytology , Cholinergic Neurons/metabolism , Coculture Techniques , GABAergic Neurons/cytology , Hippocampus/embryology , Hippocampus/growth & development , Mice , Mice, Knockout , Neural Pathways/anatomy & histology , Semaphorins/genetics , Septum of Brain/embryology , Septum of Brain/growth & development , Tissue Culture Techniques
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