Altered Network Activity Research Articles

Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in a Mecp2 mouse model for Rett syndrome.

Social memory impairments in Mecp2 knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments in Mecp2 KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in Mecp2 KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca2+-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca2+ signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs of Mecp2 KO mice showed smaller Ca2+ signals during interactions only with live mice. On the other hand, mPFC PV-INs of Mecp2 KO mice showed larger Ca2+ signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network of Mecp2 KO mice during social interactions, potentially driving their deficit in social memory.

Network Reorganization for Neurophysiological and Behavioral Recovery Following Stroke.

Stroke continues to be the main cause of motor disability worldwide. While rehabilitation has been promised to improve recovery after stroke, efficacy in clinical trials has been mixed. We need to understand the cortical recombination framework to understand how biomarkers for neurophysiological reorganized neurotechnologies alter network activity. Here, we summarize the principles of the movement network, including the current evidence of changes in the connections and function of encephalic regions, recovery from stroke and the therapeutic effects of rehabilitation. Overall, improvements or therapeutic effects in limb motor control following stroke are correlated with the effects of interhemispheric competition or compensatory models of the motor supplementary cortex. This review suggests that future research should focus on cross-regional communication and provide fundamental insights into further treatment and rehabilitation for post-stroke patients.

Atypical cortical networks in children at high-genetic risk of psychiatric and neurodevelopmental disorders

Although many genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10–17 years old. Resting-state oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, neurodevelopmental symptoms and IQ. Children with 22q11.2DS had altered network activity and connectivity in high and low frequency bands, reflecting modified local and long-range cortical circuitry. Alpha and theta band connectivity were negatively associated with ASD symptoms while frontal high frequency (gamma band) activity was positively associated with ASD symptoms. Alpha band activity was positively associated with cognitive ability. These findings suggest that haploinsufficiency at the 22q11.2 locus impacts short and long-range cortical circuits, which could be a mechanism underlying neurodevelopmental and psychiatric vulnerability in this high-risk group.

Reduced MUNC18-1 Levels, Synaptic Proteome Changes, and Altered Network Activity in STXBP1-Related Disorder Patient Neurons

BackgroundSTXBP1-related disorder (STXBP1-RD) is a neurodevelopmental disorder caused by pathogenic variants in the STXBP1 gene. Its gene product MUNC18-1 organizes synaptic vesicle exocytosis and is essential for synaptic transmission. Patients present with developmental delay, intellectual disability, and/or epileptic seizures, with high clinical heterogeneity. To date, the cellular deficits of neurons of patients with STXBP1-RD are unknown. MethodsWe combined live-cell imaging, electrophysiology, confocal microscopy, and mass spectrometry proteomics to characterize cellular phenotypes of induced pluripotent stem cell–derived neurons from 6 patients with STXBP1-RD, capturing shared features as well as phenotypic diversity among patients. ResultsNeurons from all patients showed normal in vitro development, morphology, and synapse formation, but reduced MUNC18-1 RNA and protein levels. In addition, a proteome-wide screen identified dysregulation of proteins related to synapse function and RNA processes. Neuronal networks showed shared as well as patient-specific phenotypes in activity frequency, network irregularity, and synchronicity, especially when networks were challenged by increasing excitability. No shared effects were observed in synapse physiology of single neurons except for a few patient-specific phenotypes. Similarities between functional and proteome phenotypes suggested 2 patient clusters, not explained by gene variant type. ConclusionsTogether, these data show that decreased MUNC18-1 levels, dysregulation of synaptic proteins, and altered network activity are shared cellular phenotypes of STXBP1-RD. The 2 patient clusters suggest distinctive pathobiology among subgroups of patients, providing a plausible explanation for the clinical heterogeneity. This phenotypic spectrum provides a framework for future validation studies and therapy design for STXBP1-RD.

Empirically validated theoretical analysis of visual-spatial perception under change of nervous system arousal.

Visual-spatial perception is a process for extracting the spatial relationship between objects in the environment. The changes in visual-spatial perception due to factors such as the activity of the sympathetic nervous system (hyperactivation) or parasympathetic nervous system (hypoactivation) can affect the internal representation of the external visual-spatial world. We formulated a quantitative model of the modulation of visual-perceptual space under action by hyperactivation or hypoactivation-inducing neuromodulating agents. We showed a Hill equation based relationship between neuromodulator agent concentration and alteration of visual-spatial perception utilizing the metric tensor to quantify the visual space. We computed the dynamics of the psilocybin (hyperactivation-inducing agent) and chlorpromazine (hypoactivation-inducing agent) in brain tissue. Then, we validated our quantitative model by analyzing the findings of different independent behavioral studies where subjects were assessed for alterations in visual-spatial perception under the action of psilocybin and under chlorpromazine. To validate the neuronal correlates, we simulated the effect of the neuromodulating agent on the computational model of the grid-cell network, and also performed diffusion MRI-based tractography to find the neural tracts between the cortical areas involved: V2 and the entorhinal cortex. We applied our computational model to an experiment (where perceptual alterations were measured under psilocybin) and found that for n (Hill-coefficient) = 14.8 and k = 1.39, the theoretical prediction followed experimental observations very well (χ2 test robustly satisfied, p > 0.99). We predicted the outcome of another psilocybin-based experiment using these values (n = 14.8 and k = 1.39), whereby our prediction and experimental outcomes were well corroborated. Furthermore, we found that also under hypoactivation (chlorpromazine), the modulation of the visual-spatial perception follows our model. Moreover, we found neural tracts between the area V2 and entorhinal cortex, thus providing a possible brain network responsible for encoding visual-spatial perception. Thence, we simulated the altered grid-cell network activity, which was also found to follow the Hill equation. We developed a computational model of visuospatial perceptual alterations under altered neural sympathetic/parasympathetic tone. We validated our model using analysis of behavioral studies, neuroimaging assessment, and neurocomputational evaluation. Our quantitative approach may be probed as a potential behavioral screening and monitoring methodology in neuropsychology to analyze perceptual misjudgment and mishaps by highly stressed workers.

Increased Network Inhibition in the Dentate Gyrus of Adult Neuroligin-4 Knock-Out Mice

Loss-of-function mutations in neuroligin-4 (Nlgn4), a member of the neuroligin family of postsynaptic adhesion proteins, cause autism spectrum disorder in humans. Nlgn4 knockout (KO) in mice leads to social behavior deficits and complex alterations of synaptic inhibition or excitation, depending on the brain region. In the present work, we comprehensively analyzed synaptic function and plasticity at the cellular and network levels in hippocampal dentate gyrus of Nlgn4 KO mice. Compared with wild-type littermates, adult Nlgn4 KO mice exhibited increased paired-pulse inhibition of dentate granule cell population spikes, but no impairments in excitatory synaptic transmission or short-term and long-term plasticity in vivo In vitro patch-clamp recordings in neonatal organotypic entorhino-hippocampal slice cultures from Nlgn4 KO and wild-type littermates revealed no significant differences in excitatory or inhibitory synaptic transmission, homeostatic synaptic plasticity, and passive electrotonic properties in dentate granule cells, suggesting that the increased inhibition in vivo is the result of altered network activity in the adult Nlgn4 KO. A comparison with prior studies on Nlgn 1-3 knock-out mice reveals that each of the four neuroligins exerts a characteristic effect on both intrinsic cellular and network activity in the dentate gyrus in vivo.

Alterations in theta-gamma coupling and sharp wave-ripple, signs of prodromal hippocampal network impairment in the TgF344-AD rat model.

Alzheimer's disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (Aβ) and tau, which eventually leads to dementia. Disease-modifying therapies are still lacking, due to incomplete insights into the neuropathological mechanisms of AD. Synaptic dysfunction is known to occur before cognitive symptoms become apparent and recent studies have demonstrated that imbalanced synaptic signaling drives the progression of AD, suggesting that early synaptic dysfunction could be an interesting therapeutic target. Synaptic dysfunction results in altered oscillatory activity, which can be detected with electroencephalography and electrophysiological recordings. However, the majority of these studies have been performed at advanced stages of AD, when extensive damage and cognitive symptoms are already present. The current study aimed to investigate if the hippocampal oscillatory activity is altered at pre-plaque stages of AD. The rats received stereotactic surgery to implant a laminar electrode in the CA1 layer of the right hippocampus. Electrophysiological recordings during two consecutive days in an open field were performed in 4-5-month-old TgF344-AD rats when increased concentrations of soluble Aβ species were observed in the brain, in the absence of Aβ-plaques. We observed a decreased power of high theta oscillations in TgF344-AD rats compared to wild-type littermates. Sharp wave-ripple (SWR) analysis revealed an increased SWR power and a decreased duration of SWR during quiet wake in TgF344-AD rats. The alterations in properties of SWR and the increased power of fast oscillations are suggestive of neuronal hyperexcitability, as has been demonstrated to occur during presymptomatic stages of AD. In addition, decreased strength of theta-gamma coupling, an important neuronal correlate of memory encoding, was observed in the TgF344-AD rats. Theta-gamma phase amplitude coupling has been associated with memory encoding and the execution of cognitive functions. Studies have demonstrated that mild cognitive impairment patients display decreased coupling strength, similar to what is described here. The current study demonstrates altered hippocampal network activity occurring at pre-plaque stages of AD and provides insights into prodromal network dysfunction in AD. The alterations observed could aid in the detection of AD during presymptomatic stages.

Network-Based Differences in Top-Down Multisensory Integration between Adult ADHD and Healthy Controls-A Diffusion MRI Study.

Attention-deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder neurobiologically conceptualized as a network disorder in white and gray matter. A relatively new branch in ADHD research is sensory processing. Here, altered sensory processing i.e., sensory hypersensitivity, is reported, especially in the auditory domain. However, our perception is driven by a complex interplay across different sensory modalities. Our brain is specialized in binding those different sensory modalities to a unified percept-a process called multisensory integration (MI) that is mediated through fronto-temporal and fronto-parietal networks. MI has been recently described to be impaired for complex stimuli in adult patients with ADHD. The current study relates MI in adult ADHD with diffusion-weighted imaging. Connectome-based and graph-theoretic analysis was applied to investigate a possible relationship between the ability to integrate multimodal input and network-based ADHD pathophysiology. Multishell, high-angular resolution diffusion-weighted imaging was performed on twenty-five patients with ADHD (six females, age: 30.08 (SD: 9.3) years) and twenty-four healthy controls (nine females; age: 26.88 (SD: 6.3) years). Structural connectome was created and graph theory was applied to investigate ADHD pathophysiology. Additionally, MI scores, i.e., the percentage of successful multisensory integration derived from the McGurk paradigm, were groupwise correlated with the structural connectome. Structural connectivity was elevated in patients with ADHD in network hubs mirroring altered default-mode network activity typically reported for patients with ADHD. Compared to controls, MI was associated with higher connectivity in ADHD between Heschl's gyrus and auditory parabelt regions along with altered fronto-temporal network integrity. Alterations in structural network integrity in adult ADHD can be extended to multisensory behavior. MI and the respective network integration in ADHD might represent the maturational cortical delay that extends to adulthood with respect to sensory processing.

Altered population activity and local tuning heterogeneity in auditory cortex of Cacna2d3-deficient mice.

The α2δ3 auxiliary subunit of voltage-activated calcium channels is required for normal synaptic transmission and precise temporal processing of sounds in theauditory brainstem. In mice its loss additionally leads to an inability to distinguish amplitude-modulated tones. Furthermore, loss of function of α2δ3 has been associated with autism spectrum disorder in humans. To investigate possible alterations of network activity in the higher-order auditory system in α2δ3 knockout mice, we analyzed neuronal activity patterns and topography of frequency tuning within networks of the auditory cortex (AC) using two-photon Ca2+ imaging. Compared to wild-type mice we found distinct subfield-specific alterations in the primary auditory cortex, expressed in overall lower correlations between the network activity patterns in response to different sounds as well as lower reliability of these patterns upon repetitions of the same sound. Higher AC subfields did not display these alterations but showed a higher amount of well-tuned neurons along with lower local heterogeneity of the neurons' frequency tuning. Our results provide new insight into AC network activity alterations in an autism spectrum disorder-associated mouse model.

Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function

SummaryDuplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification.

Miro1-dependent mitochondrial dynamics in parvalbumin interneurons

The spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV+) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca²+-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in PV+ interneurons and how changes in mitochondrial trafficking could alter network activity in the mouse brain. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization, while PV+ interneuron-mediated inhibition remained intact. These changes were accompanied by an increase in the ex vivo hippocampal γ-oscillation (30-80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.

A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging.

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803–814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE‐SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust age‐group‐related differences for the subsequent memory contrast, and the FADE‐SAME score additionally exhibited age‐group‐related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single‐value scores of memory‐related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging.

Alcohol reduces the activity of somatostatin interneurons in the mouse prefrontal cortex: A neural basis for its disinhibitory effect?

The prefrontal cortex (PFC) is involved in executive (“top-down”) control of behavior and its function is especially susceptible to the effects of alcohol, leading to behavioral disinhibition that is associated with alterations in decision making, response inhibition, social anxiety and working memory. The circuitry of the PFC involves a complex interplay between pyramidal neurons (PNs) and several subclasses of inhibitory interneurons (INs), including somatostatin (SST)-expressing INs. Using in vivo calcium imaging, we showed that alcohol dose-dependently altered network activity in layers 2/3 of the prelimbic subregion of the mouse PFC. Low doses of alcohol (1 g/kg, intraperitoneal, i.p.) caused moderate activation of SST INs and weak inhibition of PNs. At moderate to high doses, alcohol (2–3 g/kg) strongly inhibited the activity of SST INs in vivo, and this effect may result in disinhibition, as the activity of a subpopulation of PNs was simultaneously enhanced. In contrast, recordings in brain slices using ex vivo electrophysiology revealed no direct effect of alcohol on the excitability of either SST INs or PNs over a range of concentrations (20 and 50 mM) consistent with the blood alcohol levels reached in the in vivo experiments. This dose-dependent effect of alcohol on SST INs in vivo may reveal a neural basis for the disinhibitory effect of alcohol in the PFC mediated by other neurons within or external to the PFC circuitry.

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics.

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.

Functional connectivity between the entorhinal and posterior cingulate cortices underpins navigation discrepancies in at-risk Alzheimer's disease

Navigation processes that are selectively mediated by functional activity in the entorhinal cortex may be a marker of preclinical Alzheimer's disease (AD). Here, we tested if a short path integration paradigm can detect the strongest genetic-risk phenotype of AD in large sample of apolipoprotein E (APOE)-genotyped individuals. We also examined the associations between APOE-mediated navigation process, subjective cognitive decline, and rest-stating network connectivity. Navigation discrepancies classified 77% the APOE-genotyped cohort into their respective low-risk ε3ε3 and high-risk ε3ε4 categories. When connectivity strength between entorhinal and the posterior cingulate cortices (also a functional correlate of strongest APOE-dependant behavioral characteristics) was considered, this classification accuracy increased to 85%. Our findings present a whole picture of at-genetic-risk AD, including select impairment in path integration, self-report cognitive decline, and altered network activity that is reminiscent of the pathological spread of preclinical AD disease. These findings may have important implications for the early detection of AD.

Prickle2 and Igsf9b Coordinately Regulate the Cytoarchitecture of the Axon Initial Segment.

Prickle2 has been identified in genetic studies of subjects with autism spectrum disorder (ASD) and epilepsy, but the pathological mechanism of Prickle2 remains to be fully understood. Proteomic analysis of Prickle2 with mass spectrometry revealed twenty-eight Prickle2 interactors, including immunoglobulin superfamily member 9b (Igsf9b), in the brain. Here, because Igsf9 family proteins are associated with psychiatric diseases and seizures, we studied the physiological interaction between Prickle2 and Igsf9b. Prickle2 colocalized with Igsf9b in cultured hippocampal neurons. Knockdown of Prickle2 affected the subcellular localization of Igsf9b. Interestingly, Igsf9b localized along axonal processes in a pattern opposite to the ASD-related molecule ANK3/AnkG. AnkG is a major component of the axon initial segment (AIS), where a variety of ASD and epilepsy susceptibility proteins accumulate. Igsf9b-knockdown neurons displayed altered AnkG localization. Prickle2 depletion caused defects in AnkG and voltage-gated Na+ channel localization, resulting in altered network activity. These results support the idea that Prickle2 regulates AnkG distribution by controlling the proper localization of Igsf9b. The novel function of Prickle2 in AIS cytoarchitecture provides new insights into the shared pathology of ASD and epilepsy.Key words: Prickle2, Igsf9b, axon initial segment, neuronal excitability, ASD.

Essential role for InSyn1 in dystroglycan complex integrity and cognitive behaviors in mice.

Human mutations in the dystroglycan complex (DGC) result in not only muscular dystrophy but also cognitive impairments. However, the molecular architecture critical for the synaptic organization of the DGC in neurons remains elusive. Here, we report Inhibitory Synaptic protein 1 (InSyn1) is a critical component of the DGC whose loss alters the composition of the GABAergic synapses, excitatory/inhibitory balance in vitro and in vivo, and cognitive behavior. Association of InSyn1 with DGC subunits is required for InSyn1 synaptic localization. InSyn1 null neurons also show a significant reduction in DGC and GABA receptor distribution as well as abnormal neuronal network activity. Moreover, InSyn1 null mice exhibit elevated neuronal firing patterns in the hippocampus and deficits in fear conditioning memory. Our results support the dysregulation of the DGC at inhibitory synapses and altered neuronal network activity and specific cognitive tasks via loss of a novel component, InSyn1.

Multifaceted circuit functions of adult-born neurons.

The dentate gyrus continually produces new neurons throughout life. Behavioral studies in rodents and network models show that new neurons contribute to normal dentate functions, but there are many unanswered questions about how the relatively small population of new neurons alters network activity. Here we discuss experimental evidence that supports multiple cellular mechanisms by which adult-born neurons contribute to circuit function. Whereas past work focused on the unique intrinsic properties of young neurons, more recent studies also suggest that adult-born neurons alter the excitability of the mature neuronal population via unexpected circuit interactions.

Temporary Visual Deprivation Causes Decorrelation of Spatiotemporal Population Responses in Adult Mouse Auditory Cortex.

Although within-modality sensory plasticity is limited to early developmental periods, cross-modal plasticity can occur even in adults. In vivo electrophysiological studies have shown that transient visual deprivation (dark exposure, DE) in adult mice improves the frequency selectivity and discrimination of neurons in thalamorecipient layer 4 (L4) of primary auditory cortex (A1). Since sound information is processed hierarchically in A1 by populations of neurons, we investigated whether DE alters network activity in A1 L4 and layer 2/3 (L2/3). We examined neuronal populations in both L4 and L2/3 using in vivo two-photon calcium (Ca2+) imaging of transgenic mice expressing GCaMP6s. We find that one week of DE in adult mice increased the sound evoked responses and frequency selectivity of both L4 and L2/3 neurons. Moreover, after DE the frequency representation changed with L4 and L2/3 showing a reduced representation of cells with best frequencies (BFs) between 8 and 16 kHz and an increased representation of cells with BFs above 32 kHz. Cells in L4 and L2/3 showed decreased pairwise signal correlations (SCs) consistent with sharper tuning curves. The decreases in SCs were larger in L4 than in L2/3. The decreased pairwise correlations indicate a sparsification of A1 responses to tonal stimuli. Thus, cross-modal experience in adults can both alter the sound-evoked responses of A1 neurons and change activity correlations within A1 potentially enhancing the encoding of auditory stimuli.

Changes in excitatory and inhibitory receptor expression and network activity during induction and establishment of epilepsy in the rat Reduced Intensity Status Epilepticus (RISE) model

The RISE model is an effective system to study the underlying molecular and cellular mechanisms involved in the initiation and maintenance of epilepsy in vivo. Here we profiled the expression of excitatory and inhibitory neurotransmitter receptor subunits and synaptic scaffolding proteins in the hippocampus and temporal lobe and compared these changes with alterations in network activity at specific timepoints during epileptogenesis. Significant changes occurred in all of the ionotropic glutamate receptor subunits tested during epilepsy induction and progression and the profile of these changes differed between the hippocampus and temporal lobe. Notably, AMPAR subunits were dramatically decreased during the latent phase of epilepsy induction, matched by a profound decrease in the network response to kainate application in the hippocampus. Moreover, decreases in the GABAAβ3 subunit are consistent with a loss of inhibitory input contributing to the perturbation of excitatory/inhibitory balance and seizure generation. These data highlight the synaptic reorganisation that mediates the relative hypoexcitability prior to the manifestation of seizures and subsequent hyperexcitability when spontaneous seizures develop. These patterns of changes give new insight into the mechanisms underpinning epilepsy and provide a platform for future investigations targeting particular receptor subunits to reduce or prevent seizures.