With the wide adoption of genomic sequencing in children having seizures, an increasing number of SCN2A genetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by gene SCN2A , is predominantly expressed in the pyramidal excitatory neurons and supports action potential (AP) firing. One recurrent SCN2A genetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human-induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9-mediated genome editing. Using patch-clamping and microelectrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have...

In the article “Connecting TNF-α Signaling Pathways to iNOS Expression in a Mouse Model of Alzheimer's Disease: Relevance for the Behavioral and Synaptic Deficits Induced by Amyloid β Protein,” by Rodrigo Medeiros, Rui D. S. Prediger, Giselle F. Passos, Pablo Pandolfo, Filipe S. Duarte,

In the article “Neuropathic Pain-Like Behavior after Brachial Plexus Avulsion in Mice: The Relevance of Kinin B1 and B2 Receptors,” by Nara L. M. Quintão, Giselle F. Passos, Rodrigo Medeiros, Ana F. Paszcuk, Fabiana L. Motta, João B. Pesquero, Maria M. Campos, and João B. Calixto, which

Bilateral cochlear implants (BI-CIs) or a CI for single-sided deafness (SSD-CI; one normally functioning acoustic ear) can partially restore spatial-hearing abilities, including sound localization and speech understanding in noise. For these populations, however, interaural place-of-stimulation mismatch can occur and thus diminish binaural sensitivity that relies on interaurally frequency-matched neurons. This study examined whether plasticity—reorganization of central neural pathways over time—can compensate for peripheral interaural place mismatch. We hypothesized differential plasticity across two systems: none for binaural processing but adaptation for pitch perception toward frequencies delivered by the specific electrodes. Interaural place mismatch was evaluated in 19 BI-CI and 23 SSD-CI human subjects (both sexes) using binaural processing (interaural-time-difference discrimination with simultaneous bilateral stimulation), pitch perception (pitch ranking for single electrodes or acoustic tones with ...

Accumulating evidence in the past decade implicates histone-modifying enzymes, such as class I histone deacetylases (HDACs), in learning and memory and, recently, habit formation. However, it is unclear whether HDACs play roles in complex cognitive function. To address this issue, we examined the role of dorsal striatal HDAC5, a class II HDAC, in reward-guided decision-making and associated neural encoding in rats. We first injected adeno-associated virus to overexpress a nuclear-localized HDAC5 in dorsal striatum (DS). We then recorded neural correlates from dorsolateral striatum (DLS) as rats performed two reward-guided choice tasks, in which we manipulated either the size of or delay to reward. During these tasks, rats first learned which of two options led to the better reward and then reversed those contingencies in a second block of trials. We found that rats with HDAC5 overexpression in DS responded faster and chose higher value reward more often during the first block of trials but were less able t...

Rodrigo S. Chaves, My Tran, Andrew R. Holder, Alexandra M. Balcer, Andrea M. Dickey, et al. (see pages [10034–10053][1]) A blow to the head can deform brain tissue, stretching axons and damaging cytoskeletons. The resulting disruption of microtubule-based transport leads to the accumulation of

Traumatic brain injury (TBI) results in disrupted brain function following impact from an external force and is a risk factor for sporadic Alzheimer's disease (AD). Although neurologic symptoms triggered by mild traumatic brain injuries (mTBI), the most common form of TBI, typically resolve rapidly, even an isolated mTBI event can increase the risk to develop AD. Aberrant accumulation of amyloid β peptide (Aβ), a cleaved fragment of amyloid precursor protein (APP), is a key pathologic outcome designating the progression of AD following mTBI and has also been linked to impaired axonal transport. However, relationships among mTBI, amyloidogenesis, and axonal transport remain unclear, in part because of the dearth of human models to study the neuronal response following mTBI. Here, we implemented a custom-microfabricated device to deform neurons derived from human-induced pluripotent stem cells, derived from a cognitively unimpaired male individual, to mimic the mild stretch experienced by neurons during mTBI...

Inflammatory cells, including macrophages and microglia, synthesize and release the oxysterol 25-hydroxycholesterol (25HC), which has antiviral and immunomodulatory properties. Here, we examined the effects of lipopolysaccharide (LPS), an activator of innate immunity, on 25HC production in microglia, and the effects of LPS and 25HC on CA1 hippocampal synaptic plasticity and learning. In primary microglia, LPS markedly increases the expression of cholesterol 25-hydroxylase (Ch25h), the key enzyme involved in 25HC synthesis, and increases the levels of secreted 25HC. Wild-type microglia produced higher levels of 25HC than Ch25h knock-out (KO) microglia with or without LPS. LPS treatment also disrupts long-term potentiation (LTP) in hippocampal slices via induction of a form of NMDA receptor-dependent metaplasticity. The inhibitory effects of LPS on LTP were mimicked by exogenous 25HC, and were not observed in slices from Ch25h KO mice. In vivo , LPS treatment also disrupts LTP and inhibits one-trial learning...

Neurons in the developing visual cortex undergo progressive functional maturation as indicated by the refinement of their visual feature selectivity. However, changes of the synaptic architecture underlying the maturation of spatial visual receptive fields (RFs) per se remain largely unclear. Here, loose-patch as well as single-unit recordings in layer 4 of mouse primary visual cortex (V1) of both sexes revealed that RF development following an eye-opening period is marked by an increased proportion of cortical neurons with spatially defined RFs, together with the increased signal-to-noise ratio of spiking responses. By exploring excitatory and inhibitory synaptic RFs with whole-cell voltage-clamp recordings, we observed a balanced enhancement of both synaptic excitation and inhibition, and while the excitatory subfield size remains relatively constant during development, the inhibitory subfield is broadened. This balanced developmental strengthening of excitatory and inhibitory synaptic inputs results in ...

Retinal ganglion cells (RGCs) exhibit compartmentalized organization, receiving synaptic inputs through their dendrites and transmitting visual information from the retina to the brain through the optic nerve. Little is known about the structure of RGC axon bundles extending from individual RGC somas to the optic nerve head (ONH) and how they respond to disease insults. We recently introduced visible-light optical coherence tomography fibergraphy (vis-OCTF), a technique for directly visualizing and analyzing mouse RGC axon bundles in vivo . In this study, we validated vis-OCTF's ability to quantify RGC axon bundles with an increased number of RGCs using mice deficient in BCL2-associated X protein (BAX−/−). Next, we performed optic nerve crush (ONC) injury on wild-type (WT) mice and showed that the changes in RGC axon bundle width and thickness were location-dependent. Our work demonstrates the potential of vis-OCTF to longitudinally quantify and track RGC damage at single axon bundle level in optic neuropa...