UBE3A expression during early postnatal brain development is required for proper dorsomedial striatal maturation.

Angelman syndrome (AS) is a severe neurodevelopmental disorder (NDD) caused by loss of functional ubiquitin protein ligase E3A (UBE3A). Previous studies showed that UBE3A plays an important role in the first postnatal weeks of mouse brain development, but its precise role is unknown. Since impaired striatal maturation has been implicated in several mouse models for NDDs, we studied the importance of UBE3A in striatal maturation.

Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis.

Tuberous sclerosis complex (TSC), caused by heterozygous mutations in TSC1 or TSC2, frequently results in intractable epilepsy. Here, we made use of an inducible Tsc1-knockout mouse model, allowing us to study electrophysiological and molecular changes of Tsc1-induced epileptogenesis over time. We recorded from pyramidal neurons in the hippocampus and somatosensory cortex (L2/L3) and combined this with an analysis of transcriptome changes during epileptogenesis.

Angelman Syndrome: From Mouse Models to Therapy.

The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems.

Loss of nuclear UBE3A causes electrophysiological and behavioral deficits in mice and is associated with Angelman syndrome.

Mutations affecting the gene encoding the ubiquitin ligase UBE3A cause Angelman syndrome. Although most studies focus on the synaptic function of UBE3A, we show that UBE3A is highly enriched in the nucleus of mouse and human neurons. We found that the two major isoforms of UBE3A exhibit highly distinct nuclear versus cytoplasmic subcellular localization.

Adult Gene Reinstatement Restores the Electrophysiological Deficits of Prefrontal Cortex Layer 5 Neurons in a Mouse Model of Angelman Syndrome.

E3 ubiquitin ligase (UBE3A) levels in the brain need to be tightly regulated, as loss of functional UBE3A protein is responsible for the severe neurodevelopmental disorder Angelman syndrome (AS), whereas increased activity of UBE3A is associated with nonsyndromic autism. Given the role of mPFC in neurodevelopmental disorders including autism, we aimed to identify the functional changes resulting from loss of UBE3A in infralimbic and prelimbic mPFC areas in a mouse model of AS. Whole-cell recordings from layer 5 mPFC pyramidal neurons obtained in brain slices from adult mice of both sexes revealed that loss of UBE3A results in a strong decrease of spontaneous inhibitory transmission and increase of spontaneous excitatory transmission potentially leading to a marked excitation/inhibition imbalance.

Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity.

Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. We identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs.

Functional properties of GABA synaptic inputs onto GABA neurons in monkey prefrontal cortex.

In rodent cortex GABAA receptor (GABAAR)-mediated synapses are a significant source of input onto GABA neurons, and the properties of these inputs vary among GABA neuron subtypes that differ in molecular markers and firing patterns. Some features of cortical interneurons are different between rodents and primates, but it is not known whether inhibition of GABA neurons is prominent in the primate cortex and, if so, whether these inputs show heterogeneity across GABA neuron subtypes. We thus studied GABAAR-mediated miniature synaptic events in GABAergic interneurons in layer 3 of monkey dorsolateral prefrontal cortex (DLPFC).

Topographic mapping between basal forebrain cholinergic neurons and the medial prefrontal cortex in mice.

The basal forebrain cholinergic innervation of the medial prefrontal cortex (mPFC) is crucial for cognitive performance. However, little is known about the organization of connectivity between the basal forebrain and the mPFC in the mouse. Using focal virus injections inducing Cre-dependent enhanced yellow fluorescent protein expression in ChAT-IRES-Cre mice, we tested the hypothesis that there is a topographic mapping between the basal forebrain cholinergic neurons and their axonal projections to the mPFC.

Functional Maturation of GABA Synapses During Postnatal Development of the Monkey Dorsolateral Prefrontal Cortex.

Development of inhibition onto pyramidal cells may be crucial for the emergence of cortical network activity, including gamma oscillations. In primate dorsolateral prefrontal cortex (DLPFC), inhibitory synaptogenesis starts in utero and inhibitory synapse density reaches adult levels before birth. However, in DLPFC, the expression levels of γ-aminobutyric acid (GABA) synapse-related gene products changes markedly during development until young adult age, suggesting a highly protracted maturation of GABA synapse function.

Ventromedial prefrontal cortex pyramidal cells have a temporal dynamic role in recall and extinction of cocaine-associated memory.

In addicts, associative memories related to the rewarding effects of drugs of abuse can evoke powerful craving and drug seeking urges, but effective treatment to suppress these memories is not available. Detailed insight into the neural circuitry that mediates expression of drug-associated memory is therefore of crucial importance. Substantial evidence from rodent models of addictive behavior points to the involvement of the ventromedial prefrontal cortex (vmPFC) in conditioned drug seeking, but specific knowledge of the temporal role of vmPFC pyramidal cells is lacking.

The role of glutamatergic inputs onto parvalbumin-positive interneurons: relevance for schizophrenia.

Cognitive impairment, a core feature of schizophrenia, has been suggested to arise from a disturbance of gamma oscillations that is due to decreased neurotransmission from the parvalbumin (PV) subtype of interneurons. Indeed, PV interneurons have uniquely fast membrane and synaptic properties that are crucially important for network functions such as feedforward inhibition or gamma oscillations. The causes leading to impairment of PV neurotransmission in schizophrenia are still under investigation.

Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear.

Upon retrieval, fear memories are rendered labile and prone to modification, necessitating a restabilization process of reconsolidation to persist further. This process is also crucial for modulating both strength and content of an existing memory and forms a promising therapeutic target for fear-related disorders. However, the molecular and cellular mechanism of adaptive reconsolidation still remains obscure.

Glutamate receptor subtypes mediating synaptic activation of prefrontal cortex neurons: relevance for schizophrenia.

Schizophrenia may involve hypofunction of NMDA receptor (NMDAR)-mediated signaling, and alterations in parvalbumin-positive fast-spiking (FS) GABA neurons that may cause abnormal gamma oscillations. It was recently hypothesized that prefrontal cortex (PFC) FS neuron activity is highly dependent on NMDAR activation and that, consequently, FS neuron dysfunction in schizophrenia is secondary to NMDAR hypofunction. However, NMDARs are abundant in synapses onto PFC pyramidal neurons; thus, a key question is whether FS neuron or pyramidal cell activation is more dependent on NMDARs.

GABA transporter GAT1 prevents spillover at proximal and distal GABA synapses onto primate prefrontal cortex neurons.

The plasma membrane GABA transporter GAT1 is thought to mediate uptake of synaptically released GABA. In the primate dorsolateral prefrontal cortex (DLPFC), GAT1 expression changes significantly during development and in schizophrenia. The consequences of such changes, however, are not well understood because GAT1's role has not been investigated in primate neocortical circuits.

Dopamine D1 receptor activation regulates sodium channel-dependent EPSP amplification in rat prefrontal cortex pyramidal neurons.

Dopamine (DA) effects on prefrontal cortex (PFC) neurons are essential for the cognitive functions mediated by this cortical area. However, the cellular mechanisms of DA neuromodulation in neocortex are not well understood. We characterized the effects of D1-type DA receptor (D1R) activation on the amplification (increase in duration and area) of excitatory postsynaptic potentials (EPSPs) at depolarized potentials, in layer 5 pyramidal neurons from rat PFC.

Mediodorsal thalamic afferents to layer III of the rat prefrontal cortex: synaptic relationships to subclasses of interneurons.

The mediodorsal nucleus of the thalamus (MD) represents the main subcortical structure that projects to the prefrontal cortex (PFC) and it regulates key aspects of the cognitive functions of this region. Within the PFC, GABA local circuit neurons shape the activity patterns and hence the "memory fields" of pyramidal cells. Although the connections between the MD and PFC are well established, the ultrastructural relationships between projecting fibers from the MD and different subclasses of GABA cells in the PFC are not known.