Distinct Ventral Hippocampus Network Properties in Dissociated Cultures.

Extensive research has been focused in the past century on structural, physiological, and molecular attributes of the hippocampus. This interest was created by the unique involvement of the hippocampus in cognitive and affective functions of the brain. Functional analysis revealed that the hippocampus has divergent properties along its axial dimension to the extent that the dorsal sector (dorsal hippocampus, DH) has different connections with the rest of the brain than those of the ventral sector (VH).

Cultured Rat Hippocampal Neurons Exposed to the Mitochondrial Uncoupler Carbonyl Cyanide Chlorophenylhydrazone Undergo a Rapid, Presenilin-Dependent Change in Neuronal Properties.

Presenilin 1 (PS1) is a transmembrane proteolytic subunit of -secretase that cleaves amyloid precursor proteins. Mutations in PS1 (mPS1) are associated with early-onset familial Alzheimer's disease (AD). The link between mutated PS1, mitochondrial calcium regulation, and AD has been studied extensively in different test systems.

Exposure of Cultured Hippocampal Neurons to the Mitochondrial Uncoupler Carbonyl Cyanide Chlorophenylhydrazone Induces a Rapid Growth of Dendritic Processes.

A major route for the influx of calcium ions into neurons uses the STIM-Orai1 voltage-independent channel. Once cytosolic calcium ([Ca]i) elevates, it activates mitochondrial and endoplasmic calcium stores to affect downstream molecular pathways. In the present study, we employed a novel drug, carbonyl cyanide chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, to explore the role of mitochondria in cultured neuronal morphology.

Dynamic Regulation of Mitochondrial [Ca] in Hippocampal Neurons.

While neuronal mitochondria have been studied extensively in their role in health and disease, the rules that govern calcium regulation in mitochondria remain somewhat vague. In the present study using cultured rat hippocampal neurons transfected with the mtRCaMP mitochondrial calcium sensor, we investigated the effects of cytosolic calcium surges on the dynamics of mitochondrial calcium ([Ca]m). Cytosolic calcium ([Ca]c) was measured using the high affinity sensor Fluo-2.

Mechanisms Driving the Emergence of Neuronal Hyperexcitability in Fragile X Syndrome.

Hyperexcitability is a shared neurophysiological phenotype across various genetic neurodevelopmental disorders, including Fragile X syndrome (FXS). Several patient symptoms are associated with hyperexcitability, but a puzzling feature is that their onset is often delayed until their second and third year of life. It remains unclear how and why hyperexcitability emerges in neurodevelopmental disorders.

Impaired Functional Connectivity Underlies Fragile X Syndrome.

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by a developmentally regulated silencing of the gene, but its effect on human neuronal network development and function is not fully understood. Here, we isolated isogenic human embryonic stem cell (hESC) subclones-one with a full FX mutation and one that is free of the mutation (control) but shares the same genetic background-differentiated them into induced neurons (iNs) by forced expression of , and compared the functional properties of the derived neuronal networks. High-throughput image analysis demonstrates that FX-iNs have significantly smaller cell bodies and reduced arborizations than the control.

Neuronal circuits overcome imbalance in excitation and inhibition by adjusting connection numbers.

The interplay between excitation and inhibition is crucial for neuronal circuitry in the brain. Inhibitory cell fractions in the neocortex and hippocampus are typically maintained at 15 to 30%, which is assumed to be important for stable dynamics. We have studied systematically the role of precisely controlled excitatory/inhibitory (E/I) cellular ratios on network activity using mice hippocampal cultures.

Calcium Sensors STIM1 and STIM2 Regulate Different Calcium Functions in Cultured Hippocampal Neurons.

There are growing indications for the involvement of calcium stores in the plastic properties of neurons and particularly in dendritic spines of central neurons. The store-operated calcium entry (SOCE) channels are assumed to be activated by the calcium sensor stromal interaction molecule (STIM)which leads to activation of its associated Orai channel. There are two STIM species, and the differential role of the two in SOCE is not entirely clear.

Allostatic gene regulation of inhibitory synaptic factors in the rat ventral hippocampus in a juvenile/adult stress model of psychopathology.

Early life stress is an important vulnerability factor for the development of anxiety disorders, depression and late-onset cognitive decline. Recently, we demonstrated that juvenile stress (JS) lastingly enhanced long-term potentiation via reduction of steady-state glutamine synthetase mRNA expression and the associated dysregulation of the astrocytic glutamate-glutamine cycle in the rat ventral CA1. We now investigated the regulation of steady-state mRNA expression of neuronal gene products that determine GABAergic and glutamatergic neurotransmission in layers of the ventral and dorsal CA1 after JS.

False Opposing Fear Memories Are Produced as a Function of the Hippocampal Sector Where Glucocorticoid Receptors Are Activated.

Injection of corticosterone (CORT) in the dorsal hippocampus (DH) can mimic post-traumatic stress disorder (PTSD)-related memory in mice: both maladaptive hypermnesia for a salient but irrelevant simple cue and amnesia for the traumatic context. However, accumulated evidence indicates a functional dissociation within the hippocampus such that contextual learning is primarily associated with the DH whereas emotional processes are more linked to the ventral hippocampus (VH). This suggests that CORT might have different effects on fear memories as a function of the hippocampal sector preferentially targeted and the type of fear learning (contextual vs.

ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus.

Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits.

Presenilin 1 Regulates [Ca]i and Mitochondria/ER Interaction in Cultured Rat Hippocampal Neurons.

Mutations in the presenilin 1 (PS1) gene are a major trigger of familial Alzheimer's disease (AD), yet the mechanisms affected by mutated PS1 causing cognitive decline are not yet elucidated. In the present study, we compared rat hippocampal neurons in culture, transfected with PS1 or with mutant (M146V) PS1 (mPS1) plasmids in several neuronal functions. Initially, we confirmed earlier observations that mPS1-expressing neurons are endowed with fewer mature "mushroom" spines and more filopodial immature protrusions.

The Interactome of Palmitoyl-Protein Thioesterase 1 (PPT1) Affects Neuronal Morphology and Function.

Palmitoyl-protein thioesterase 1 (PPT1) is a depalmitoylation enzyme that is mutated in cases of neuronal ceroid lipofuscinosis (NCL). The hallmarks of the disease include progressive neurodegeneration and blindness, as well as seizures. In the current study, we identified 62 high-confident PPT1-binding proteins.

Patch-Clamp Recordings from Human Embryonic Stem Cells-Derived Fragile X Neurons.

Performing electrophysiological recordings from human neurons that have been differentiated in vitro, as compared to primary cultures, raises many challenges. However, patch-clamp recording from neurons derived from stem cells provides an abundance of valuable information, reliably and fast. Here, we describe a protocol that is used successfully in our lab for recording from both control and Fragile X neurons, derived in vitro from human embryonic stem cells.

Synaptopodin Deficiency Ameliorates Symptoms in the 3xTg Mouse Model of Alzheimer's Disease.

Disruption in calcium homeostasis is linked to several pathologies and is suggested to play a pivotal role in the cascade of events leading to Alzheimer's disease (AD). Synaptopodin (SP) residing in dendritic spines has been associated with ryanodine receptor (RyR), such that spines lacking SP release less calcium from stores. In this work, we mated SPKO with 3xTg mice (3xTg/SPKO) to test the effect of SP deficiency in the AD mouse.

Learning Deficits in Adult Mitochondria Carrier Homolog 2 Forebrain Knockout Mouse.

Mitochondrial Carrier Homolog 2 (MTCH2) acts as a receptor for the BH3 interacting-domain death agonist (BID) in the mitochondrial outer membrane. Loss of MTCH2 affects mitochondria energy metabolism and function. MTCH2 forebrain conditional KO (MTCH2 BKO) display a deficit in hippocampus-dependent cognitive functions.

Calcium stores regulate excitability in cultured rat hippocampal neurons.

Extracellular calcium ions support synaptic activity but also reduce excitability of central neurons. In the present study, the effect of calcium on excitability was explored in cultured hippocampal neurons. CaCl injected by pressure in the vicinity of a neuron that is bathed only in MgCl as the main divalent cation caused a depolarizing shift in action potential threshold and a reduction in excitability.

Cannabidiol Regulates Long Term Potentiation Following Status Epilepticus: Mediation by Calcium Stores and Serotonin.

Epilepsy is a devastating disease, with cognitive and emotional consequences that are not curable. In recent years, it became apparent that cannabinoids help patients to cope with epilepsy. We have studied the effects of cannabidiol (CBD) on the ability to produce long term potentiation (LTP) in stratum radiatum of CA1 region of the mouse hippocampus.

Astrocyte disruption of neurovascular communication is linked to cortical damage in an animal model of multiple sclerosis.

To elucidate mechanisms contributing to cortical pathology in multiple sclerosis (MS), we investigated neurovascular aberrations, in particular the association of astrocytes with cortical neurons and blood vessels, in mice induced with experimental autoimmune encephalomyelitis (EAE). Blood-brain barrier (BBB) dysfunction was evident by leakage of the tracer sodium fluorescein, along with reduced expression of claudin-5 by endothelial cells and desmin by pericytes. Immunohistological and ultrastructural analyses revealed detachment of the astroglial cell bodies from the blood vessels and loss of their connections with both the blood vessels and the neuronal synapses.

Building Bridges through Science.

Science is ideally suited to connect people from different cultures and thereby foster mutual understanding. To promote international life science collaboration, we have launched "The Science Bridge" initiative. Our current project focuses on partnership between Western and Middle Eastern neuroscience communities.

Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy.

This review focuses on the inter- and transgenerational effects of stress experience prior to and during gestation. We provide an overview of findings from studies in humans as well as in animal models on brain structural and physiological functions and on the development of cognitive and executive functions. We also discuss the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the braińs reward system.

Complex modulation by stress of the effect of seizures on long term potentiation in mouse hippocampal slices.

Stress has a profound effect on ability to express neuronal plasticity, learning, and memory. Likewise, epileptic seizures lead to massive changes in brain connectivity, and in ability to undergo long term changes in reactivity to afferent stimulation. In this study, we analyzed possible long lasting interactions between a stressful experience and reactivity to pilocarpine, on the ability to produce long term potentiation (LTP) in a mouse hippocampus.