Neuroligins (NLGNs) are a class of postsynaptic cell adhesion molecules that interact with presynaptic neurexins (NRXNs) and regulate synapse function. NLGN4 is a member of the NLGN family and consists of a unique amino acid sequence in humans that is not evolutionarily well conserved in rodents. The human-specific NLGN4 gene has been reported to be mutated in many patients with autism and other neurodevelopmental disorders. However, it remained unclear how these mutations might alter the molecular properties of NLGN4 and affect synaptic transmission in human neurons. Here, we describe a severely autistic male patient carrying a single amino acid substitution (R101Q) in the NLGN4 gene. When expressed in HEK293 cells, the R101Q mutation in NLGN4 did not affect its binding affinity for NRXNs or its capacity to form homodimers. This mutation, however, impaired the maturation of NLGN4 protein by inhibiting N-linked glycosylation at an adjacent residue (N102), which is conserved in all NLGNs. As a result, the R...

Dysregulation of proteins involved in synaptic plasticity is associated with pathologies in the CNS, including psychiatric disorders. The bed nucleus of the stria terminalis (BNST), a brain region of the extended amygdala circuit, has been identified as the critical hub responsible for fear responses related to stress coping and pathologic systems states. Here, we report that one particular nucleus, the oval nucleus of the BNST (ovBNST), is rich in brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor. Whole-cell patch-clamp recordings of neurons from male mouse ovBNST in vitro showed that the BDNF/TrkB interaction causes a hyperpolarizing shift of the membrane potential from resting value, mediated by an inwardly rectifying potassium current, resulting in reduced neuronal excitability in all major types of ovBNST neurons. Furthermore, BDNF/TrkB signaling mediated long-term depression (LTD) at postsynaptic sites in ovBNST neurons. LTD of ovBNST neurons was prevented by ...

Neuronal and network-level hyperexcitability is commonly associated with increased levels of amyloid-β (Aβ) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study, we tested the hypothesis that the oligomeric form of amyloid-β (oAβ42), interacting with α7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α7β2-nAChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice, and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically relevant level of oAβ42 showed enhanced ne...

Excessive fear learning and generalized, extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in male mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear conditioning or memory consolidation resulted in enhanced cue-related fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cue-related fear recall subsequently, potentially via altered activity of downstream regions. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin (SOM), but not corticotropin- releasing factor (CRF) neurons of the BNST, which was accompanied by increased fear generalization. Our fi...

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common focal epilepsy syndrome, yet the cause of this disease remains unknown. Now recognized as a mild epileptic encephalopathy, children exhibit sleep-activated focal epileptiform discharges and cognitive difficulties during the active phase of the disease. The association between the abnormal electrophysiology and sleep suggests disruption to thalamocortical circuits. Thalamocortical circuit dysfunction resulting in pathological epileptiform activity could hinder the production of sleep spindles, a brain rhythm essential for memory processes. Despite this pathophysiologic connection, the relationship between spindles and cognitive symptoms in epileptic encephalopathies has not been previously evaluated. A significant challenge limiting such work has been the poor performance of available automated spindle detection methods in the setting of sharp activities, such as epileptic spikes. Here, we validate a robust new method to accurately mea...

Appropriate termination of the photoresponse in image-forming photoreceptors and downstream neurons is critical for an animal to achieve high temporal resolution. Although the cellular and molecular mechanisms of termination in image-forming photoreceptors have been extensively studied in Drosophila , the underlying mechanism of termination in their downstream large monopolar cells (LMCs) remains less explored. Here, we show that synaptic acetylcholine (ACh) signaling, from both amacrine cells (ACs) and L4 neurons, facilitates the rapid repolarization of L1 and L2 neurons. Intracellular recordings in female flies show that blocking synaptic ACh output from either ACs or L4 neurons leads to slow repolarization of L1 and L2 neurons. Genetic and electrophysiological studies in both male and female flies determine that L2 neurons express ACh receptors and directly receive ACh signaling. Moreover, our results demonstrate that synaptic ACh signaling from both ACs and L4 neurons simultaneously facilitates ERG ter...

One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams’ health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups’ developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduct...

DYT1 dystonia is a hereditary neurological movement disorder characterized by uncontrollable muscle contractions. It is caused by a heterozygous mutation in Torsin A ( TOR1A ), a gene encoding a membrane-embedded ATPase. While animal models provide insights into disease mechanisms, significant species-dependent differences exist since animals with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-specific cholinergic motor neurons (MNs) that are generated through either direct conversion of patients’ skin fibroblasts or differentiation of induced pluripotent stem cells (iPSCs). These human MNs with the heterozygous TOR1A mutation show reduced neurite length and branches, markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport of mRNAs and proteins, whereas they lack the perinuclear “blebs” that are often observed in animal models. Furthermore, we uncover that the nuclear lamina protein LMNB1 is upregulate...

Flexible adaptation to changing environments is a representative executive control function implicated in the fronto-parietal network that requires appropriate extraction of goal-relevant information through perception of the external environment. It remains unclear, however, how the flexibility is achieved under situations where goal-relevant information is uncertain. To address this issue, the current study examined neural mechanisms for task switching in which task-relevant information involved perceptual uncertainty. Twenty-eight human participants of both sexes alternated behavioral tasks in which they judged motion direction or color of visually presented colored dot stimuli that moved randomly. Task switching was associated with fronto-parietal regions in the left hemisphere, and perception of ambiguous stimuli involved contralateral homologous fronto-parietal regions. On the other hand, in stimulus-modality-dependent occipitotemporal regions, task coding information was increased during task switch...