Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostas...

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down’s syndrome, Alzheimer’s and Parkinson’s diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, in order to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3−CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q, a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processe...

At any given moment our sensory systems receive multiple, often rhythmic, inputs from the environment. Processing of temporally structured events in one sensory modality can guide both behavioural and neural processing of events in other sensory modalities, but whether this occurs remains unclear. Here, we used human electroencephalography (EEG) to test the cross-modal influences of a continuous auditory frequency-modulated (FM) sound on visual perception and visual cortical activity. We report systematic fluctuations in perceptual discrimination of brief visual stimuli in line with the phase of the FM sound. We further show that this rhythmic modulation in visual perception is related to an accompanying rhythmic modulation of neural activity recorded over visual areas. Importantly, in our task, perceptual and neural visual modulations occurred without any abrupt and salient onsets in the energy of the auditory stimulation and without any rhythmic structure in the visual stimulus. As such, the results prov...

Social behavior is coordinated by a network of brain regions, including those involved in the perception of social stimuli and those involved in complex functions, such as inferring perceptual and mental states and controlling social interactions. The properties and function of many of these regions in isolation are relatively well understood, but less is known about how these regions interact while processing dynamic social interactions. To investigate whether the functional connectivity between brain regions is modulated by social context, we collected fMRI data from male monkeys ( Macaca mulatta ) viewing videos of social interactions labeled as “affiliative,” “aggressive,” or “ambiguous.” We show activation related to the perception of social interactions along both banks of the superior temporal sulcus, parietal cortex, medial and lateral frontal cortex, and the caudate nucleus. Within this network, we show that fronto-temporal functional connectivity is significantly modulated by social context. Cruc...

Neuropeptide secretion from dense-core vesicles (DCVs) controls many brain functions. Several components of the DCV exocytosis machinery have recently been identified, but the participation of a SEC1/MUNC18 (SM) protein has remained elusive. Here, we tested the ability of the three exocytic SM proteins expressed in the mammalian brain, MUNC18-1/2/3, to support neuropeptide secretion. We quantified DCV exocytosis at a single vesicle resolution on action potential (AP) train-stimulation in mouse CNS neurons (of unknown sex) using pHluorin-tagged and/or mCherry-tagged neuropeptide Y (NPY) or brain-derived neurotrophic factor (BDNF). Conditional inactivation of Munc18-1 abolished all DCV exocytosis. Expression of MUNC18-1, but not MUNC18-2 or MUNC18-3, supported DCV exocytosis in Munc18-1 null neurons. Heterozygous (HZ) inactivation of Munc18-1 , as a model for reduced MUNC18-1 expression, impaired DCV exocytosis, especially during the initial phase of train-stimulation, when the release was maximal. These dat...

The lateral (LA) and basolateral (BL) nuclei of the amygdala regulate emotional behaviors. Despite their dissimilar extrinsic connectivity, they are often combined, perhaps because their cellular composition is similar to that of the cerebral cortex, including excitatory principal cells reciprocally connected with fast-spiking interneurons (FSIs). In the cortex, this microcircuitry produces gamma oscillations that support information processing and behavior. We tested whether this was similarly the case in the rat (males) LA and BL using extracellular recordings, biophysical modeling, and behavioral conditioning. During periods of environmental assessment, both nuclei exhibited gamma oscillations that stopped upon initiation of active behaviors. Yet, BL exhibited more robust spontaneous gamma oscillations than LA. The greater propensity of BL to generate gamma resulted from several microcircuit differences, especially the proportion of FSIs and their interconnections with principal cells. Furthermore, gamm...

Vocal learning species must form and extensively hone associations between sounds and social contingencies. In songbirds, dopamine signaling guides song motor production, variability, and motivation, but it is unclear how dopamine regulates fundamental auditory associations for learning new sounds. We hypothesized that dopamine regulates learning in the auditory pallium, in part by interacting with local neuroestradiol signaling. Here, we show that zebra finch auditory neurons frequently coexpress D1 receptor (D1R) protein, neuroestradiol-synthase, GABA, and parvalbumin (PV). Auditory classical conditioning increased neuroplasticity gene induction in D1R-positive neurons. In vitro , D1R pharmacological activation reduced the amplitude of GABAergic and glutamatergic currents and increased the latter's frequency. In vivo , D1R activation reduced the firing of putative interneurons, increased the firing of putative excitatory neurons, and made both neuronal types unable to adapt to novel stimuli. Together, th...

Amacrine cells are interneurons composing the most diverse cell class in the mammalian retina. They help encode visual features, such as edges or directed motion, by mediating excitatory and inhibitory interactions between input (i.e., bipolar) and output (i.e., ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, metabolic regulation, and neurovascular control. Here, we report that, in mouse retina (of either sex), an abundant, though previously unstudied inhibitory amacrine cell is coupled directly to Müller glia. Electron microscopic reconstructions of this amacrine type revealed chemical synapses with known retinal cell types and extensive associations with Müller glia, the processes of which often completely ensheathe the neurites of this amacrine cell. Microinjecting small tracer molecules into the somas of these amacrine cells led to selective labeling of nearby Müller glia, leading us to sugg...

Visual word recognition, at a minimum, involves the processing of word form and lexical information. Opinions diverge on the spatiotemporal distribution of and interaction between the two types of information. Feedforward theory argues that they are processed sequentially, whereas interactive theory advocates that lexical information is processed fast and modulates early word form processing. To distinguish between the two theories, we applied stereoelectroencephalography (SEEG) to 33 human adults with epilepsy (25 males and eight females) during visual lexical decisions. The stimuli included real words (RWs), pseudowords (PWs) with legal radical positions, nonwords (NWs) with illegal radical positions, and stroked-changed words (SWs) in Chinese. Word form and lexical processing were measured by the word form effect (PW versus NW) and lexical effect (RW versus PW), respectively. Gamma-band (60 ∼ 140 Hz) SEEG activity was treated as an electrophysiological measure. A word form effect was found in eight left...