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1. Inhibition of AKT Signaling Alters βIV Spectrin Distribution at the AIS and Increases Neuronal Excitability

   https://doi.org/10.3389/fnmol.2021.643860  

   Di Re, Jessica; Hsu, Wei-Chun J.; Kayasandik, Cihan B.; Fularczyk, Nickolas; James, T. F.; Nenov, Miroslav N.; Negi, Pooran; Marosi, Mate; Scala, Federico; Prasad, Saurabh; et al (June 2021, Frontiers in Molecular Neuroscience)

   null (Ed.)

   The axon initial segment (AIS) is a highly regulated subcellular domain required for neuronal firing. Changes in the AIS protein composition and distribution are a form of structural plasticity, which powerfully regulates neuronal activity and may underlie several neuropsychiatric and neurodegenerative disorders. Despite its physiological and pathophysiological relevance, the signaling pathways mediating AIS protein distribution are still poorly studied. Here, we used confocal imaging and whole-cell patch clamp electrophysiology in primary hippocampal neurons to study how AIS protein composition and neuronal firing varied in response to selected kinase inhibitors targeting the AKT/GSK3 pathway, which has previously been shown to phosphorylate AIS proteins. Image-based features representing the cellular pattern distribution of the voltage-gated Na+ (Nav) channel, ankyrin G, βIV spectrin, and the cell-adhesion molecule neurofascin were analyzed, revealing βIV spectrin as the most sensitive AIS protein to AKT/GSK3 pathway inhibition. Within this pathway, inhibition of AKT by triciribine has the greatest effect on βIV spectrin localization to the AIS and its subcellular distribution within neurons, a phenotype that Support Vector Machine classification was able to accurately distinguish from control. Treatment with triciribine also resulted in increased excitability in primary hippocampal neurons. Thus, perturbations to signaling mechanisms within the AKT pathway contribute to changes in βIV spectrin distribution and neuronal firing that may be associated with neuropsychiatric and neurodegenerative disorders. 

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2. The potassium channel subunit K _v β1 serves as a major control point for synaptic facilitation

   https://doi.org/10.1073/pnas.2000790117  

   Cho, In Ha; Panzera, Lauren C.; Chin, Morven; Alpizar, Scott A.; Olveda, Genaro E.; Hill, Robert A.; Hoppa, Michael B. (November 2020, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Analysis of the presynaptic action potential’s (AP syn ) role in synaptic facilitation in hippocampal pyramidal neurons has been difficult due to size limitations of axons. We overcame these size barriers by combining high-resolution optical recordings of membrane potential, exocytosis, and Ca 2+ in cultured hippocampal neurons. These recordings revealed a critical and selective role for K v 1 channel inactivation in synaptic facilitation of excitatory hippocampal neurons. Presynaptic K v 1 channel inactivation was mediated by the K v β1 subunit and had a surprisingly rapid onset that was readily apparent even in brief physiological stimulation paradigms including paired-pulse stimulation. Genetic depletion of K v β1 blocked all broadening of the AP syn during high-frequency stimulation and eliminated synaptic facilitation without altering the initial probability of vesicle release. Thus, using all quantitative optical measurements of presynaptic physiology, we reveal a critical role for presynaptic K v channels in synaptic facilitation at presynaptic terminals of the hippocampus upstream of the exocytic machinery. 

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3. Time-dependent homeostatic mechanisms underlie brain-derived neurotrophic factor action on neural circuitry

   https://doi.org/10.1038/s42003-023-05638-9  

   O’Neill, Kate_M; Anderson, Erin_D; Mukherjee, Shoutik; Gandu, Srinivasa; McEwan, Sara_A; Omelchenko, Anton; Rodriguez, Ana_R; Losert, Wolfgang; Meaney, David_F; Babadi, Behtash; et al (December 2023, Communications Biology)

   Abstract Plasticity and homeostatic mechanisms allow neural networks to maintain proper function while responding to physiological challenges. Despite previous work investigating morphological and synaptic effects of brain-derived neurotrophic factor (BDNF), the most prevalent growth factor in the central nervous system, how exposure to BDNF manifests at the network level remains unknown. Here we report that BDNF treatment affects rodent hippocampal network dynamics during development and recovery from glutamate-induced excitotoxicity in culture. Importantly, these effects are not obvious when traditional activity metrics are used, so we delve more deeply into network organization, functional analyses, and in silico simulations. We demonstrate that BDNF partially restores homeostasis by promoting recovery of weak and medium connections after injury. Imaging and computational analyses suggest these effects are caused by changes to inhibitory neurons and connections. From our in silico simulations, we find that BDNF remodels the network by indirectly strengthening weak excitatory synapses after injury. Ultimately, our findings may explain the difficulties encountered in preclinical and clinical trials with BDNF and also offer information for future trials to consider. 

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4. Phasic cholinergic signaling promotes emergence of local gamma rhythms in excitatory–inhibitory networks

   https://doi.org/10.1111/ejn.14744  

   Lu, Yiqing; Sarter, Martin; Zochowski, Michal; Booth, Victoria (May 2020, European Journal of Neuroscience)

   Abstract Recent experimental results have shown that the detection of cues in behavioral attention tasks relies on transient increases of acetylcholine (ACh) release in frontal cortex and cholinergically driven oscillatory activity in the gamma frequency band (Howe et al. Journal of Neuroscience, 2017, 37, 3215). The cue‐induced gamma rhythmic activity requires stimulation of M1 muscarinic receptors. Using biophysical computational modeling, we show that a network of excitatory (E) and inhibitory (I) neurons that initially displays asynchronous firing can generate transient gamma oscillatory activity in response to simulated brief pulses of ACh. ACh effects are simulated as transient modulation of the conductance of an M‐type K⁺current which is blocked by activation of muscarinic receptors and has significant effects on neuronal excitability. The ACh‐induced effects on the M current conductance,g_Ks, change network dynamics to promote the emergence of network gamma rhythmicity through a Pyramidal‐Interneuronal Network Gamma mechanism. Depending on connectivity strengths between and among E and I cells, gamma activity decays with the simulatedg_Kstransient modulation or is sustained in the network after theg_Kstransient has completely dissipated. We investigated the sensitivity of the emergent gamma activity to synaptic strengths, external noise and simulated levels ofg_Ksmodulation. To address recent experimental findings that cholinergic signaling is likely spatially focused and dynamic, we show that localizedg_Ksmodulation can induce transient changes of cellular excitability in local subnetworks, subsequently causing population‐specific gamma oscillations. These results highlight dynamical mechanisms underlying localization of ACh‐driven responses and suggest that spatially localized, cholinergically induced gamma may contribute to selectivity in the processing of competing external stimuli, as occurs in attentional tasks. 

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5. Heterozygous Deletion of Epilepsy Gene KCNQ2 Has Negligible Effects on Learning and Memory

   https://doi.org/10.3389/fnbeh.2022.930216  

   Tracy, Gregory C.; Wilton, Angelina R.; Rhodes, Justin S.; Chung, Hee Jung (July 2022, Frontiers in Behavioral Neuroscience)

   Neuronal K_v7/Potassium Voltage-Gated Channel Subfamily Q (KCNQ) potassium channels underlie M-current that potently suppresses repetitive and burst firing of action potentials (APs). They are mostly heterotetramers of K_v7.2 and K_v7.3 subunits in the hippocampus and cortex, the brain regions important for cognition and behavior. Underscoring their critical roles in inhibiting neuronal excitability, autosomal dominantly inherited mutations in Potassium Voltage-Gated Channel Subfamily Q Member 2 (KCNQ2) and Potassium Voltage-Gated Channel Subfamily Q Member 3 (KCNQ3) genes are associated with benign familial neonatal epilepsy (BFNE) in which most seizures spontaneously remit within months without cognitive deficits.De novomutations inKCNQ2also cause epileptic encephalopathy (EE), which is characterized by persistent seizures that are often drug refractory, neurodevelopmental delay, and intellectual disability. Heterozygous expression of EE variants ofKCNQ2is recently shown to induce spontaneous seizures and cognitive deficit in mice, although it is unclear whether this cognitive deficit is caused directly by K_v7 disruption or by persistent seizures in the developing brain as a consequence of K_v7 disruption. In this study, we examined the role of K_v7 channels in learning and memory by behavioral phenotyping of theKCNQ2^+/−mice, which lack a single copy ofKCNQ2but dos not display spontaneous seizures. We found that bothKCNQ2^+/−and wild-type (WT) mice showed comparable nociception in the tail-flick assay and fear-induced learning and memory during a passive inhibitory avoidance (IA) test and contextual fear conditioning (CFC). Both genotypes displayed similar object location and recognition memory. These findings together provide evidence that heterozygous loss ofKCNQ2has minimal effects on learning or memory in mice in the absence of spontaneous seizures. 

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