Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission.

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission.

Sex-Specific Roles of Hypocretin Receptor Signaling in CRF Neurons on Alcohol Drinking, Anxiety, and BNST Neuronal Excitability.

Alcohol use disorder (AUD) is characterized by compulsive alcohol consumption and negative emotional states during withdrawal, often perpetuating a cycle of addiction through arousal dysfunction. The hypocretin/orexin (Hcrt) neuropeptide system, a key regulator of arousal, has been implicated in these processes, particularly in its interactions with corticotropin-releasing factor (CRF) neurons within the bed nucleus of the stria terminalis (BNST). We investigated the role of Hcrt receptor signaling in CRF neurons in modulating alcohol intake, anxiety behaviors, and BNST excitability, with a focus on sex-specific differences.

Low-Frequency Stimulation of Trpv1-Lineage Peripheral Afferents Potentiates the Excitability of Spino-Periaqueductal Gray Projection Neurons.

High-threshold dorsal root ganglion (HT DRG) neurons fire at low frequencies during inflammatory injury, and low-frequency stimulation (LFS) of HT DRG neurons selectively potentiates excitatory synapses onto spinal neurons projecting to the periaqueductal gray (spino-PAG). Here, in male and female mice, we have identified an underlying peripheral sensory population driving this plasticity and its effects on the output of spino-PAG neurons. We provide the first evidence that Trpv1-lineage sensory neurons predominantly induce burst firing, a unique mode of neuronal activity, in lamina I spino-PAG projection neurons.

Function of Excitatory Periaqueductal Gray Synapses in the Ventral Tegmental Area following Inflammatory Injury.

Manipulating the activity of ventral tegmental area (VTA) dopamine (DA) neurons can drive nocifensive reflexes, and their firing rates are reduced following noxious stimuli. However, the pain-relevant inputs to the VTA remain incompletely understood. In this study, we used male and female mice in combination with identified dopamine and GABA neurons in the VTA that receive excitatory inputs from the periaqueductal gray (PAG), a nexus of ascending pain information.

Somatodendritic Release of Cholecystokinin Potentiates GABAergic Synapses Onto Ventral Tegmental Area Dopamine Cells.

Background: Neuropeptides are contained in nearly every neuron in the central nervous system and can be released not only from nerve terminals but also from somatodendritic sites. Cholecystokinin (CCK), among the most abundant neuropeptides in the brain, is expressed in the majority of midbrain dopamine neurons. Despite this high expression, CCK function within the ventral tegmental area (VTA) is not well understood.

Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.

Locus coeruleus (LC) is among the first brain areas to degenerate in Alzheimer's disease and Parkinson's disease; however, the underlying causes for the vulnerability of LC neurons are not well defined. Here we report a novel mechanism of degeneration of LC neurons caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 Deficiency is a newly-recognized childhood neurometabolic disorder.

Adolescent sleep shapes social novelty preference in mice.

Sleep disturbances frequently occur in neurodevelopmental disorders such as autism, but the developmental role of sleep is largely unexplored, and a causal relationship between developmental sleep defects and behavioral consequences in adulthood remains elusive. Here, we show that in mice, sleep disruption (SD) in adolescence, but not in adulthood, causes long-lasting impairment in social novelty preference. Furthermore, adolescent SD alters the activation and release patterns of dopaminergic neurons in the ventral tegmental area (VTA) in response to social novelty.

Hyperexcitable arousal circuits drive sleep instability during aging.

Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness.

Selective control of synaptically-connected circuit elements by all-optical synapses.

Understanding percepts, engrams and actions requires methods for selectively modulating synaptic communication between specific subsets of interconnected cells. Here, we develop an approach to control synaptically connected elements using bioluminescent light: Luciferase-generated light, originating from a presynaptic axon terminal, modulates an opsin in its postsynaptic target. Vesicular-localized luciferase is released into the synaptic cleft in response to presynaptic activity, creating a real-time Optical Synapse.

Endogenous Opsin 3 (OPN3) Protein Expression in the Adult Brain Using a Novel OPN3-mCherry Knock-In Mouse Model.

The opsins have been studied extensively for their functions in visual phototransduction; however, the mechanisms underlying extraocular opsin signaling remain poorly understood. The first mammalian extraocular opsin to be discovered, opsin 3 (OPN3), was found in the brain more than two decades ago, yet its function remains unknown. A significant hindrance to studying OPN3 has been a lack of specific antibodies against mammalian OPN3, resulting in an incomplete understanding of its expression in the brain.

Periaqueductal Gray and Rostromedial Tegmental Inhibitory Afferents to VTA Have Distinct Synaptic Plasticity and Opiate Sensitivity.

The ventral tegmental area (VTA) is a major target of addictive drugs and receives multiple GABAergic projections originating outside the VTA. We describe differences in synaptic plasticity and behavior when optogenetically driving two opiate-sensitive GABAergic inputs to the VTA, the rostromedial tegmental nucleus (RMTg), and the periaqueductal gray (PAG). Activation of GABAergic RMTg terminals in the VTA in vivo is aversive, and low-frequency stimulation induces long-term depression in vitro.

NMDA receptor activation induces long-term potentiation of glycine synapses.

Of the fast ionotropic synapses, glycinergic synapses are the least well understood, but are vital for the maintenance of inhibitory signaling in the brain and spinal cord. Glycinergic signaling comprises half of the inhibitory signaling in the spinal cord, and glycinergic synapses are likely to regulate local nociceptive processing as well as the transmission to the brain of peripheral nociceptive information. Here we have investigated the rapid and prolonged potentiation of glycinergic synapses in the superficial dorsal horn of young male and female mice after brief activation of NMDA receptors (NMDARs).

Properties of neurons in the superficial laminae of trigeminal nucleus caudalis.

The trigeminal nucleus caudalis (TNc) receives extensive afferent innervation from peripheral sensory neurons of the trigeminal ganglion (TG), and is the first central relay in the circuitry underpinning orofacial pain. Despite the initial characterization of the neurons in the superficial laminae, many questions remain. Here we report on electrophysiological properties of 535 superficial lamina I/II TNc neurons.

Two-Pronged Control of the Dorsal Raphe by the VTA.

In this issue of Neuron, Li et al. (2019) distinguish two separable GABAergic projections from the ventral tegmental area (VTA) to the dorsal raphe nucleus (DRN), with differential μ-opioid receptor regulation, each targeting different postsynaptic neurons and promoting opposing behavioral states.

Long-Term Depression Induced by Optogenetically Driven Nociceptive Inputs to Trigeminal Nucleus Caudalis or Headache Triggers.

The peripheral trigeminovascular pathway mediates orofacial and craniofacial pain and projects centrally to the brainstem trigeminal nucleus caudalis (TNc). Sensitization of this pathway is involved in many pain conditions, but little is known about synaptic plasticity at its first central synapse. We have taken advantage of optogenetics to investigate plasticity selectively evoked at synapses of nociceptive primary afferents onto TNc neurons.

Persistent but Labile Synaptic Plasticity at Excitatory Synapses.

Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons.

Synaptic function and plasticity in identified inhibitory inputs onto VTA dopamine neurons.

Ventral tegmental area (VTA) dopaminergic neurons are key components of the reward pathway, and their activity is powerfully controlled by a diverse array of inhibitory GABAergic inputs. Two major sources of GABAergic nerve terminals within the VTA are local VTA interneurons and neurons in the rostromedial tegmental nucleus (RMTg). Here, using optogenetics, we compared synaptic properties of GABAergic synapses on VTA dopamine neurons using selective activation of afferents that originate from these two cell populations.

Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress.

Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs.

Three-Dimensional Neural Spheroid Culture: An In Vitro Model for Cortical Studies.

There is a high demand for in vitro models of the central nervous system (CNS) to study neurological disorders, injuries, toxicity, and drug efficacy. Three-dimensional (3D) in vitro models can bridge the gap between traditional two-dimensional culture and animal models because they present an in vivo-like microenvironment in a tailorable experimental platform. Within the expanding variety of sophisticated 3D cultures, scaffold-free, self-assembled spheroid culture avoids the introduction of foreign materials and preserves the native cell populations and extracellular matrix types.

Yin and Yang: unsilencing synapses to control cocaine seeking.

In this issue of Neuron, Ma et al. (2014) show that long-term depression of two independent prefrontal cortical inputs to nucleus accumbens modifies behavioral responses controlling incubation of cocaine craving. Intriguingly, one input increases while the other attenuates behavioral responses, hinting that both "prorelapse" and "antirelapse" pathways are strengthened after cocaine self-administration.

Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking.

Background: Dopaminergic neurons in the ventral tegmental area of the brain are an important site of convergence of drugs and stress. We previously identified a form of long-term potentiation of gamma-aminobutyric acid (GABA)ergic synapses on these neurons (LTPGABA). Our studies have shown that exposure to acute stress blocks this LTP and that reversal of the block of LTPGABA is correlated with prevention of stress-induced reinstatement of cocaine-seeking behavior.

Long-term potentiation of glycinergic synapses triggered by interleukin 1β.

Long-term potentiation (LTP) is a persistent increase in synaptic strength required for many behavioral adaptations, including learning and memory, visual and somatosensory system functional development, and drug addiction. Recent work has suggested a role for LTP-like phenomena in the processing of nociceptive information in the dorsal horn and in the generation of central sensitization during chronic pain states. Whereas LTP of glutamatergic and GABAergic synapses has been characterized throughout the central nervous system, to our knowledge there have been no reports of LTP at mammalian glycinergic synapses.

Stress and VTA synapses: implications for addiction and depression.

While stressful experiences are a part of everyone's life, they can also exact a major toll on health. Stressful life experiences are associated with increased substance abuse, and there exists significant co-morbidity between mental illness and substance use disorders [N.D.

Christianson syndrome protein NHE6 modulates TrkB endosomal signaling required for neuronal circuit development.

Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Na⁺/H⁺ exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown.