Synaptic control of temporal processing in the Drosophila olfactory system

Temporal filtering of sensory stimuli is a key neural computation, but the way such filters are implemented within the brain is unclear. One potential mechanism for implementing temporal filters is short-term synaptic plasticity, which is governed in part by the expression of pre-synaptic proteins that position synaptic vesicles at different distances to calcium channels. Here we leveraged the Drosophila olfactory system to directly test the hypothesis that short-term synaptic plasticity shapes temporal filtering of sensory stimuli. We used optogenetic activation to drive olfactory receptor neuron (ORN) activity with high temporal precision and knocked down the presynaptic priming factor unc13A specifically in ORNs. We found that this manipulation specifically decreases and delays transmission of high frequencies, leading to poorer encoding of distant plume filaments. We replicate this effect using a previously-developed model of transmission at this synapse, which features two components with different depression kinetics. Finally, we show that upwind running, a key component of odor source localization, is preferentially driven by high-frequency stimulus fluctuations, and this response is reduced by unc13A knock-down in ORNs. Our work links the extraction of particular temporal features of a sensory stimulus to the expression of particular presynaptic molecules.

Formation and synaptic control of active transient working memory representations

Neural representations of working memory maintain information temporarily and make it accessible for processing. This is most feasible in active, spiking representations. State-of-the-art modeling frameworks, however, reproduce working memory representations that are either transient but non-active or active but non-transient. Here, we analyze a biologically motivated working memory model which shows that synaptic short-term plasticity and noise emerging from spiking networks can jointly produce a working memory representation that is both active and transient. We investigate the effect of a synaptic signaling mechanism whose dysregulation is related to schizophrenia and show how it controls transient working memory duration through presynaptic, astrocytic and postsynaptic elements. Our findings shed light on the computational capabilities of healthy working memory function and offer a possible mechanistic explanation for how molecular alterations observed in psychiatric diseases such as schizophrenia can lead to working memory impairments.

Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus

DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDARs drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3A1. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively, the data show that plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation.

Psychiatric Disorders and lncRNAs: A Synaptic Match

Psychiatric disorders represent a heterogeneous class of multifactorial mental diseases whose origin entails a pathogenic integration of genetic and environmental influences. Incidence of these pathologies is dangerously high, as more than 20% of the Western population is affected. Despite the diverse origins of specific molecular dysfunctions, these pathologies entail disruption of fine synaptic regulation, which is fundamental to behavioral adaptation to the environment. The synapses, as functional units of cognition, represent major evolutionary targets. Consistently, fine synaptic tuning occurs at several levels, involving a novel class of molecular regulators known as long non-coding RNAs (lncRNAs). Non-coding RNAs operate mainly in mammals as epigenetic modifiers and enhancers of proteome diversity. The prominent evolutionary expansion of the gene number of lncRNAs in mammals, particularly in primates and humans, and their preferential neuronal expression does represent a driving force that enhanced the layering of synaptic control mechanisms. In the last few years, remarkable alterations of the expression of lncRNAs have been reported in psychiatric conditions such as schizophrenia, autism, and depression, suggesting unprecedented mechanistic insights into disruption of fine synaptic tuning underlying severe behavioral manifestations of psychosis. In this review, we integrate literature data from rodent pathological models and human evidence that proposes the biology of lncRNAs as a promising field of neuropsychiatric investigation.

Synaptic control of spinal GRPR+neurons by local and long-range inhibitory inputs

Spinal gastrin-releasing peptide receptor-expressing (GRPR+) neurons play an essential role in itch signal processing. However, the circuit mechanisms underlying the modulation of spinal GRPR+neurons by direct local and long-range inhibitory inputs remain elusive. Using viral tracing and electrophysiological approaches, we dissected the neural circuits underlying the inhibitory control of spinal GRPR+neurons. We found that spinal galanin+GABAergic neurons form inhibitory synapses with GRPR+neurons in the spinal cord and play an important role in gating the GRPR+neuron-dependent itch signaling pathway. Spinal GRPR+neurons also receive inhibitory inputs from local neurons expressing neuronal nitric oxide synthase (nNOS). Moreover, spinal GRPR+neurons are gated by strong inhibitory inputs from the rostral ventromedial medulla. Thus, both local and long-range inhibitory inputs could play important roles in gating itch processing in the spinal cord by directly modulating the activity of spinal GRPR+neurons.

Synaptic control of DNA-methylation involves activity-dependent degradation of DNMT3a1 in the nucleus

DNA-methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3a1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDAR drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3a1 and results in deficits of promoter methylation of activity-dependent genes, synaptic plasticity as well as memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively the data show that GluN2A containing NMDAR control synapse-to-nucleus signaling that links plasticity-relevant signals to activity-dependent DNA-methylation involved in memory formation.

Synaptic co-transmission of acetylcholine and GABA regulates hippocampal states

SummaryThe basal forebrain cholinergic system is widely assumed to control cortical functions via non-synaptic transmission of a single neurotransmitter, acetylcholine. Yet, using immune-electron tomographic, molecular anatomical, optogenetic and physiological techniques, we find that mouse hippocampal cholinergic terminals invariably establish synapses and their vesicles dock at synapses only. We demonstrate that these synapses do not co-release but co-transmit GABA and acetylcholine via different vesicles, whose release is triggered by distinct calcium channels. This co-transmission evokes fast composite postsynaptic potentials, which are mutually cross-regulated by presynaptic auto-receptors and display different short-term plasticity. The GABAergic component alone effectively suppresses hippocampal sharp wave-ripples and epileptiform activity. The synaptic nature of the forebrain cholinergic system with differentially regulated, fast, GABAergic and cholinergic co-transmission suggests a hitherto unrecognized level of synaptic control over cortical states. This novel model of hippocampal cholinergic neurotransmission could form the basis for alternative pharmacotherapies after cholinergic deinnervation seen in neurodegenerative disorders.Supplementary materials are attached after the main text.

Synaptic control of the shape of the motoneuron pool input-output function

Although motoneurons have often been considered to be fairly linear transducers of synaptic input, recent evidence suggests that strong persistent inward currents (PICs) in motoneurons allow neuromodulatory and inhibitory synaptic inputs to induce large nonlinearities in the relation between the level of excitatory input and motor output. To try to estimate the possible extent of this nonlinearity, we developed a pool of model motoneurons designed to replicate the characteristics of motoneuron input-output properties measured in medial gastrocnemius motoneurons in the decerebrate cat with voltage-clamp and current-clamp techniques. We drove the model pool with a range of synaptic inputs consisting of various mixtures of excitation, inhibition, and neuromodulation. We then looked at the relation between excitatory drive and total pool output. Our results revealed that the PICs not only enhance gain but also induce a strong nonlinearity in the relation between the average firing rate of the motoneuron pool and the level of excitatory input. The relation between the total simulated force output and input was somewhat more linear because of higher force outputs in later-recruited units. We also found that the nonlinearity can be increased by increasing neuromodulatory input and/or balanced inhibitory input and minimized by a reciprocal, push-pull pattern of inhibition. We consider the possibility that a flexible input-output function may allow motor output to be tuned to match the widely varying demands of the normal motor repertoire. NEW & NOTEWORTHY Motoneuron activity is generally considered to reflect the level of excitatory drive. However, the activation of voltage-dependent intrinsic conductances can distort the relation between excitatory drive and the total output of a pool of motoneurons. Using a pool of realistic motoneuron models, we show that pool output can be a highly nonlinear function of synaptic input but linearity can be achieved through adjusting the time course of excitatory and inhibitory synaptic inputs.