A voltage-based Event-Timing-Dependent Plasticity rule accounts for LTP subthreshold and suprathreshold for dendritic spikes in CA1 pyramidal neurons.

Long-term potentiation (LTP) is a synaptic mechanism involved in learning and memory. Experiments have shown that dendritic sodium spikes (Na-dSpikes) are required for LTP in the distal apical dendrites of CA1 pyramidal cells. On the other hand, LTP in perisomatic dendrites can be induced by synaptic input patterns that can be both subthreshold and suprathreshold for Na-dSpikes. It is unclear whether these results can be explained by one unifying plasticity mechanism. Here, we show in biophysically and morphologically realistic compartmental models of the CA1 pyramidal cell that these forms of LTP can be fully accounted for by a simple plasticity rule. We call it the voltage-based Event-Timing-Dependent Plasticity (ETDP) rule. The presynaptic event is the presynaptic spike or release of glutamate. The postsynaptic event is the local depolarization that exceeds a certain plasticity threshold. Our model reproduced the experimentally observed LTP in a variety of protocols, including local pharmacological inhibition of dendritic spikes by tetrodotoxin (TTX). In summary, we have provided a validation of the voltage-based ETDP, suggesting that this simple plasticity rule can be used to model even complex spatiotemporal patterns of long-term synaptic plasticity in neuronal dendrites.

Dorsal-Ventral Gradient of Activin Regulates Strength of GABAergic Inhibition along Longitudinal Axis of Mouse Hippocampus in an Activity-Dependent Fashion.

The functional and neurophysiological distinction between the dorsal and ventral hippocampus affects also GABAergic inhibition. In line with this notion, ventral CA1 pyramidal cells displayed a more dynamic and effective response to inhibitory input compared to their dorsal counterparts. We posit that this difference is effected by the dorsal-ventral gradient of activin A, a member of the transforming growth factor-ß family, which is increasingly recognized for its modulatory role in brain regions involved in cognitive functions and affective behavior. Lending credence to this hypothesis, we found that in slices from transgenic mice expressing a dominant-negative mutant of activin receptor IB (dnActRIB), inhibitory transmission was enhanced only in CA1 neurons of the dorsal hippocampus, where the basal activin A level is much higher than in the ventral hippocampus. We next asked how a rise in endogenous activin A would affect GABAergic inhibition along the longitudinal axis of the hippocampus. We performed ex vivo recordings in wild-type and dnActRIB mice after overnight exposure to an enriched environment (EE), which engenders a robust increase in activin A levels in both dorsal and ventral hippocampi. Compared to control mice from standard cages, the behaviorally induced surge in activin A produced a decline in ventral inhibition, an effect that was absent in slices from dnActRIB mice. Underscoring the essential role of activin in the EE-associated modulation of ventral inhibition, this effect was mimicked by acute application of recombinant activin A in control slices. In summary, both genetic and behavioral manipulations of activin receptor signaling affected the dorsal-ventral difference in synaptic inhibition, suggesting that activin A regulates the strength of GABAergic inhibition in a region-specific fashion.

Sex-dimorphic effects of biogenesis of lysosome-related organelles complex-1 deficiency on mouse perinatal brain development.

The function(s) of the Biogenesis of Lysosome-related Organelles Complex-1 (BLOC-1) during brain development is to date largely unknown. Here, we investigated how its absence alters the trajectory of postnatal brain development using as model the pallid mouse. Most of the defects observed early postnatally in the mutant mice were more prominent in males than in females and in the hippocampus. Male mutant mice, but not females, had smaller brains as compared to sex-matching wild types at postnatal day 1 (P1), this deficit was largely recovered by P14 and P45. An abnormal cytoarchitecture of the pyramidal cell layer of the hippocampus was observed in P1 pallid male, but not female, or juvenile mice (P45), along with severely decreased expression levels of the radial glial marker Glutamate-Aspartate Transporter. Transcriptomic analyses showed that the overall response to the lack of functional BLOC-1 was more pronounced in hippocampi at P1 than at P45 or in the cerebral cortex. These observations suggest that absence of BLOC-1 renders males more susceptible to perinatal brain maldevelopment and although most abnormalities appear to have been resolved in juvenile animals, still permanent defects may be present, resulting in faulty neuronal circuits, and contribute to previously reported cognitive and behavioral phenotypes in adult BLOC-1-deficient mice.

Regulation of Neuronal Na+/K+-ATPase by Specific Protein Kinases and Protein Phosphatases.

The Na+/K+-ATPase (NKA) is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na+ and K+ electrochemical gradients across the plasmalemma of living cells. Numerous studies in non-neuronal tissues have shown that this transport mechanism is reversibly regulated by phosphorylation/dephosphorylation of the catalytic α subunit and/or associated proteins. In neurons, Na+/K+ transport by NKA is essential for almost all neuronal operations, consuming up to two-thirds of the neuron's energy expenditure. However, little is known about its cellular regulatory mechanisms. Here we have used an electrophysiological approach to monitor NKA transport activity in male rat hippocampal neurons in situ We report that this activity is regulated by a balance between serine/threonine phosphorylation and dephosphorylation. Phosphorylation by the protein kinases PKG and PKC inhibits NKA activity, whereas dephosphorylation by the protein phosphatases PP-1 and PP-2B (calcineurin) reverses this effect. Given that these kinases and phosphatases serve as downstream effectors in key neuronal signaling pathways, they may mediate the coupling of primary messengers, such as neurotransmitters, hormones, and growth factors, to the NKAs, through which multiple brain functions can be regulated or dysregulated.SIGNIFICANCE STATEMENT The Na+/K+-ATPase (NKA), known as the "Na+ pump," is a ubiquitous membrane-bound enzyme responsible for generating and maintaining the Na+ and K+ electrochemical gradients across the plasma membrane of living cells. In neurons, as in most types of cells, the NKA generates the negative resting membrane potential, which is the basis for almost all aspects of cellular function. Here we used an electrophysiological approach to monitor physiological NKA transport activity in single hippocampal pyramidal cells in situ We have found that neuronal NKA activity is oppositely regulated by phosphorylation and dephosphorylation, and we have identified the main protein kinases and phosphatases mediating this regulation. This fundamental form of NKA regulation likely plays a role in multiple brain functions.

Involvement of intracellular Zn2+ signaling in LTP at perforant pathway-CA1 pyramidal cell synapse.

Physiological significance of synaptic Zn2+ signaling was examined at perforant pathway-CA1 pyramidal cell synapses. In vivo long-term potentiation (LTP) at perforant pathway-CA1 pyramidal cell synapses was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. Perforant pathway LTP was not attenuated under perfusion with CaEDTA (10 mM), an extracellular Zn2+ chelator, but attenuated under perfusion with ZnAF-2DA (50 µM), an intracellular Zn2+ chelator, suggesting that intracellular Zn2+ signaling is required for perforant pathway LTP. Even in rat brain slices bathed in CaEDTA in ACSF, intracellular Zn2+ level, which was measured with intracellular ZnAF-2, was increased in the stratum lacunosum-moleculare where perforant pathway-CA1 pyramidal cell synapses were contained after tetanic stimulation. These results suggest that intracellular Zn2+ signaling, which originates in internal stores/proteins, is involved in LTP at perforant pathway-CA1 pyramidal cell synapses. Because the influx of extracellular Zn2+ , which originates in presynaptic Zn2+ release, is involved in LTP at Schaffer collateral-CA1 pyramidal cell synapses, synapse-dependent Zn2+ dynamics may be involved in plasticity of postsynaptic CA1 pyramidal cells.

Activation of the PACAP/PAC1 Signaling Pathway Accelerates the Repair of Impaired Spatial Memory Caused by an Ultradian Light Cycle.

The mechanism of light-induced spatial memory deficits, as well as whether rhythmic expression of the pituitary adenylyl cyclase-activating polypeptides (PACAP)-PAC1 pathway influenced by light is related to this process, remains unclear. Here, we aimed to investigate the role of the PACAP-PAC1 pathway in light-mediated spatial memory deficits. Animals were first housed under a T24 cycle (12 h light:12 h dark), and then light conditions were transformed to a T7 cycle (3.5 h light:3.5 h dark) for at least 4 weeks. The spatial memory function was assessed using the Morris water maze (MWM). In line with behavioral studies, rhythmic expression of the PAC1 receptor and glutamate receptors in the hippocampal CA1 region was assessed by western blotting, and electrophysiology experiments were performed to determine the influence of the PACAP-PAC1 pathway on neuronal excitability and synaptic signaling transmission. Spatial memory was deficient after mice were exposed to the T7 light cycle. Rhythmic expression of the PAC1 receptor was dramatically decreased, and the excitability of CA1 pyramidal cells was decreased in T7 cycle-housed mice. Compensation with PACAP1-38, a PAC1 receptor agonist, helped T7 cycle-housed mouse CA1 pyramidal cells recover neuronal excitability to normal levels, and cannulas injected with PACAP1-38 shortened the time to find the platform in MWM. Importantly, the T7 cycle decreased the frequency of AMPA receptor-mediated excitatory postsynaptic currents. In conclusion, the PACAP-PAC1 pathway is an important protective factor modulating light-induced spatial memory function deficits, affecting CA1 pyramidal cell excitability and excitatory synaptic signaling transmission.

Abnormal Sleep Architecture and Hippocampal Circuit Dysfunction in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and single-gene cause of autism spectrum disorder. The Fmr1 null mouse models much of the human disease including hyperarousal, sensory hypersensitivity, seizure activity, and hippocampus-dependent cognitive impairment. Sleep architecture is disorganized in FXS patients, but has not been examined in Fmr1 knockout (Fmr1-KO) mice. Hippocampal neural activity during sleep, which is implicated in memory processing, also remains uninvestigated in Fmr1-KO mice. We performed in vivo electrophysiological studies of freely behaving Fmr1-KO mice to assess neural activity, in the form of single-unit spiking and local field potential (LFP), within the hippocampal CA1 region during multiple differentiated sleep and wake states. Here, we demonstrate that Fmr1-KO mice exhibited a deficit in rapid eye movement sleep (REM) due to a reduction in the frequency of bouts of REM, consistent with sleep architecture abnormalities of FXS patients. Fmr1-KO CA1 pyramidal cells (CA1-PCs) were hyperactive in all sleep and wake states. Increased low gamma power in CA1 suggests that this hyperactivity was related to increased input to CA1 from CA3. By contrast, slower sharp-wave ripple events (SWRs) in Fmr1-KO mice exhibited longer event duration, slower oscillation frequency, with reduced CA1-PC firing rates during SWRs, yet the incidence rate of SWRs remained intact. These results suggest abnormal neuronal activity in the Fmr1-KO mouse during SWRs, and hyperactivity during other wake and sleep states, with likely adverse consequences for memory processes.

Influx of extracellular Zn(2+) into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation.

Physiological significance of synaptic Zn(2+) signaling was examined in the CA1 of young rats. In vivo CA1 long-term potentiation (LTP) was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. In vivo CA1 LTP was inhibited under perfusion with CaEDTA and ZnAF-2DA, extracellular and intracellular Zn(2+) chelators, respectively, suggesting that the influx of extracellular Zn(2+) is required for in vivo CA1 LTP induction. The increase in intracellular Zn(2+) was chelated with intracellular ZnAF-2 in the CA1 1h after local injection of ZnAF-2DA into the CA1, suggesting that intracellular Zn(2+) signaling induced during learning is blocked with intracellular ZnAF-2 when the learning was performed 1h after ZnAF-2DA injection. Object recognition was affected when training of object recognition test was performed 1h after ZnAF-2DA injection. These data suggest that intracellular Zn(2+) signaling in the CA1 is required for object recognition memory via LTP. Surprisingly, in vivo CA1 LTP was affected under perfusion with 0.1-1µM ZnCl2, unlike the previous data that in vitro CA1 LTP was enhanced in the presence of 1-5µM ZnCl2. The influx of extracellular Zn(2+) into CA1 pyramidal cells has bidirectional action in CA1 LTP. The present study indicates that the degree of extracellular Zn(2+) influx into CA1 neurons is critical for LTP and cognitive performance.

Frequency-dependent signal processing in apical dendrites of hippocampal CA1 pyramidal cells.

Depending on an animal's behavioral state, hippocampal CA1 pyramidal cells receive distinct patterns of excitatory and inhibitory synaptic inputs. The time-dependent changes in the frequencies of these inputs and the nonuniform distribution of voltage-gated channels lead to dynamic fluctuations in membrane conductance. In this study, using a whole-cell patch-clamp method, we attempted to record and analyze the frequency dependencies of membrane responsiveness in Wistar rat hippocampal CA1 pyramidal cells following noise current injection directly into dendrites and somata under pharmacological blockade of all synaptic inputs. To estimate the frequency-dependent properties of membrane potential, membrane impedance was determined from the voltage response divided by the input current in the frequency domain. The cell membrane of most neurons showed low-pass filtering properties in all regions. In particular, the properties were strongly expressed in the somata or proximal dendrites. Moreover, the data revealed nonuniform distribution of dendritic impedance, which was high in the intermediate segment of the apical dendritic shaft (∼220-260µm from the soma). The low-pass filtering properties in the apical dendrites were more enhanced by membrane depolarization than those in the somata. Coherence spectral analysis revealed high coherence between the input signal and the output voltage response in the theta-gamma frequency range, and large lags emerged in the distal dendrites in the gamma frequency range. Our results suggest that apical dendrites of hippocampal CA1 pyramidal cells integrate synaptic inputs according to the frequency components of the input signal along the dendritic segments receiving the inputs.