Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.

Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs.

Reduction in hippocampal GABAergic transmission in a low birth weight rat model of depression.

Prenatal stress is believed to increase the risk of developing neuropsychiatric disorders, including major depression. Adverse genetic and environmental impacts during early development, such as glucocorticoid hyper-exposure, can lead to changes in the foetal brain, linked to mental illnesses developed in later life. Dysfunction in the GABAergic inhibitory system is associated with depressive disorders.

Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α.

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α).

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits.

The striatum integrates motor behavior using a well-defined microcircuit whose individual components are independently affected in several neurological diseases. The glial cell line-derived neurotrophic factor (GDNF), synthesized by striatal interneurons, and Sonic hedgehog (Shh), produced by the dopaminergic neurons of the substantia nigra (DA SNpc), are both involved in the nigrostriatal maintenance but the reciprocal neurotrophic relationships among these neurons are only partially understood. To define the postnatal neurotrophic connections among fast-spiking GABAergic interneurons (FS), cholinergic interneurons (ACh), and DA SNpc, we used a genetically induced mouse model of postnatal DA SNpc neurodegeneration and separately eliminated Smoothened (Smo), the obligatory transducer of Shh signaling, in striatal interneurons.

Toward the Inner Nanostructure of a Secretory Vesicle.

The release of chemical mediators is an essential element of cell-to-cell communication. Signaling molecules such as neurotransmitters and hormones are stored in membrane-bound organelles called secretory vesicles. Some of these organelles can store molecules at high concentrations, overcoming the osmotic shock that could burst the organelle.

A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development.

Different dynamin blockers interfere with distinct phases of synaptic endocytosis during stimulation in motoneurones.

Key Points: Neurotransmitter release requires a tight coupling between synaptic vesicle exocytosis and endocytosis with dynamin being a key protein in that process. We used imaging techniques to examine the time course of endocytosis at mouse motor nerve terminals expressing synaptopHluorin, a genetically encoded reporter of the synaptic vesicle cycle. We separated two sequential phases of endocytosis taking place during the stimulation train: early and late endocytosis.

Presynaptic plasticity as a hallmark of rat stress susceptibility and antidepressant response.

Two main questions are important for understanding and treating affective disorders: why are certain individuals susceptible or resilient to stress, and what are the features of treatment response and resistance? To address these questions, we used a chronic mild stress (CMS) rat model of depression. When exposed to stress, a fraction of rats develops anhedonic-like behavior, a core symptom of major depression, while another subgroup of rats is resilient to CMS. Furthermore, the anhedonic-like state is reversed in about half the animals in response to chronic escitalopram treatment (responders), while the remaining animals are resistant (non-responder animals).

Neurexin dysfunction in adult neurons results in autistic-like behavior in mice.

Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism.

BDNF Depresses Excitability of Parvalbumin-Positive Interneurons through an M-Like Current in Rat Dentate Gyrus.

In addition to their classical roles in neuronal growth, survival and differentiation, neurotrophins are also rapid regulators of excitability, synaptic transmission and activity-dependent synaptic plasticity. We have recently shown that mature BDNF (Brain Derived Neurotrophic Factor), but not proBDNF, modulates the excitability of interneurons in dentate gyrus within minutes. Here, we used brain slice patch-clamp recordings to study the mechanisms through which BDNF modulates the firing of interneurons in rat dentate gyrus by binding to TrkB receptors.

Positive modulation of δ-subunit containing GABA(A) receptors in mouse neurons.

δ-subunit containing extrasynaptic GABA(A) receptors are potential targets for modifying neuronal activity in a range of brain disorders. With the aim of gaining more insight in synaptic and extrasynaptic inhibition, we used a new positive modulator, AA29504, of δ-subunit containing GABA(A) receptors in mouse neurons in vitro and in vivo. Whole-cell patch-clamp recordings were carried out in the dentate gyrus in mouse brain slices.

Motorneurons require cysteine string protein-α to maintain the readily releasable vesicular pool and synaptic vesicle recycling.

Cysteine string protein-α (CSP-α) is a synaptic vesicle protein that prevents activity-dependent neurodegeneration by poorly understood mechanisms. We have studied the synaptic vesicle cycle at the motor nerve terminals of CSP-α knock-out mice expressing the synaptopHluorin transgene. Mutant nerve terminals fail to sustain prolonged release and the number of vesicles available to be released decreases.

Diminution of voltage threshold plays a key role in determining recruitment of oculomotor nucleus motoneurons during postnatal development.

The size principle dictates the orderly recruitment of motoneurons (Mns). This principle assumes that Mns of different sizes have a similar voltage threshold, cell size being the crucial property in determining neuronal recruitment. Thus, smaller neurons have higher membrane resistance and require a lower depolarizing current to reach spike threshold.

Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the central nervous system. Symptomatic and presymptomatic ALS patients demonstrate cortical hyperexcitability, which raises the possibility that alterations in inhibitory gamma-aminobutyric acid (GABA)ergic system could underlie this dysfunction. Here, we studied the GABAergic system in cortex using patch-clamp recordings in the wobbler mouse, a model of ALS.

Effect of gene dosage on single-cell hippocampal electrophysiology in a murine model of SSADH deficiency (gamma-hydroxybutyric aciduria).

Human and murine succinic semialdehyde dehydrogenase (SSADH; gamma-hydroxybutyric (GHB) aciduria) deficiency represents an epileptic disorder associated with hyperGABA- and hyperGHB-ergic states. Despite significant neurotransmitters alterations, well-defined single-cell electrophysiological studies, aimed to provide insight into regional neuropathology, have been lacking. In this study, we characterized the effect of residual SSADH enzyme function/increased GABA levels on single-cell hippocampal electrophysiology in SSADH+/+ (wild-type; WT), SSADH+/- (heterozygous; HET), and SSADH-/- (knock-out; KO) mice.

Hippocampal GABAergic dysfunction in a rat chronic mild stress model of depression.

In major depression, one line of research indicates that a dysfunctional GABAergic inhibitory system is linked to the appearance of depressive symptoms. However, as the mechanistic details of such GABAergic deficit are largely unknown, we undertook a functional investigation of the GABAergic system in the rat chronic mild stress model of depression. Adult rats were exposed to an eight-week long stress protocol leading to anhedonic-like behavior.

Mature BDNF, but not proBDNF, reduces excitability of fast-spiking interneurons in mouse dentate gyrus.

Mature BDNF and its precursor proBDNF may both be secreted to exert opposite effects on synaptic plasticity in the hippocampus. However, it is unknown how proBDNF and mature BDNF affect the excitability of GABAergic interneurons and thereby regulate GABAergic inhibition. We made recordings of GABAergic spontaneous IPSCs (sIPSCs) in mouse dentate gyrus granule cells and found that chronic or acute BDNF reductions led to large increases in the sIPSC frequencies, which were TTX (tetrodotoxin) sensitive and therefore action-potential driven.

Changes in somatodendritic morphometry of rat oculomotor nucleus motoneurons during postnatal development.

This work investigates the somatodendritic shaping of rat oculomotor nucleus motoneurons (Mns) during postnatal development. The Mns were functionally identified in slice preparation, intracellularly injected with neurobiotin, and three-dimensionally reconstructed. Most of the Mns (approximately 85%) were multipolar and the rest (approximately 15%) bipolar.

Muscarinic modulation of recruitment threshold and firing rate in rat oculomotor nucleus motoneurons.

Above recruitment threshold, ocular motoneurons (Mns) show a firing rate linearly related with eye position. Current hypothesis suggests that synaptic inputs are determinant for establishing the recruitment threshold and firing rate gain in these Mns. We investigated this proposal by studying the cholinergic modulation in oculomotor nucleus Mns by intracellular recordings in rat brain slice preparation.

Phasic and tonic firing properties in rat oculomotor nucleus motoneurons, studied in vitro.

Alert-chronic studies show that ocular motoneurons (Mns) exhibit a phasic and tonic firing correlated with eye saccade-velocity and position (fixation), respectively. Differences in the phasic and tonic firing among Mns depend on synaptic inputs and/or the intrinsic membrane properties. We have used in vitro slice preparation to investigate the contribution of membrane properties to firing properties of Wistar rat oculomotor nucleus Mns.

Changes during the postnatal development in physiological and anatomical characteristics of rat motoneurons studied in vitro.

The postnatal maturation of rat brainstem (oculomotor and hypoglossal nuclei) and spinal motoneurons, based on data collected from in vitro studies, is reviewed here. Membrane input resistance diminishes with age, but to a greater extent for hypoglossal than for oculomotor motoneurons. The time constant of the membrane diminishes with age in a similar fashion for both oculomotor and hypoglossal motoneurons.