Dentate Gyrus Local Circuit is Implicated in Learning Under Stress—a Role for Neurofascin

Zitman, Femke M.P.; Lucas, Morgan; Trinks, Sabine; Grosse-Ophoff, Laura; Kriebel, Martin; Volkmer, Hansjürgen; Richter‐Levin, Gal

doi:10.1007/s12035-014-9044-7

Cited by 11 publications

(10 citation statements)

References 26 publications

(36 reference statements)

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“…A second example is the use of neurofascin to specifically modulate feed-back inhibition onto the DG by axo-axonic chandelier interneurons without affecting feed forward inhibition. The authors took advantage of restricted expression of neurofascin in the axon initial segment that is primarily innervated by axo-axonic chandelier interneurons and found that downregulation of neurofascin decreased feed-back inhibition onto the DG to impair learning (Zitman et al, 2014).…”

Section: Re-engineering Intrinsic and Extrinsic Connectivity Of The Dmentioning

confidence: 99%

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

Besnard

Sahay

2015

Neuropsychopharmacol

192

159

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The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)-CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal-cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD.

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Section: Re-engineering Intrinsic and Extrinsic Connectivity Of The Dmentioning

confidence: 99%

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

Besnard

Sahay

2015

Neuropsychopharmacol

192

159

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“…One possibility to control GABAergic inhibitory transmission of AACs emerges by manipulating neurofascin (NF) (Kriebel et al , 2011; Zitman et al , 2014). Neurofascin is a cell adhesion molecule belonging to the L1 subfamily of immunoglobulins (Kriebel et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

“…There, NF has been implicated in maintaining action potential initiation (Zonta et al , 2011) and in stabilizing inhibitory synapses by regulating the postsynaptic scaffold protein gephyrin (Burkarth et al , 2007; Kriebel et al , 2011). Knockdown of NF at the AIS decreased gephyrin clustering, which was associated with reduced expression of the GABA A receptor subunit β 2/3 at the postsynaptic site and GAD65 at the inhibitory presynapse (Zitman et al , 2014). Within the dentate gyrus (DG), such a modulation of GABAergic inhibitory transmission at the AIS via NF knockdown altered feedback inhibition measured by paired-pulse stimulation while feed-forward inhibition remained unchanged.…”

Section: Introductionmentioning

confidence: 99%

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GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Saha

Knapp

Chakraborty

et al. 2016

Neuropsychopharmacol

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Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum–BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum–BLA–LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

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“…In the cortex, the axonal "cartridges" of synaptic boutons that form onto the AIS are generally found on the more distal AIS domain, where the AP is thought to initiate (9). Although there is little information on the role of these interneurons in network function, they have been implicated in a number of events, including driving negative feedback in the dentate gyrus (10), modulating the emergence of sharp waves in the hippocampus (11), providing complex inhibitory-excitatory feedforward loops in the cortex (12), as well as shunting and filtering out APs backpropagating from ectopic initiation sites in the hippocampus (13). In addition, there is an ongoing debate as to whether axoaxonic synapses depolarize or hyperpolarize postsynaptic pyramidal neurons (14), although in conditions mimicking in vivo-like oscillations, they act mainly as inhibitors of excitability (15).…”

mentioning

confidence: 99%

Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output

Wefelmeyer

Cattaert

Burrone

2015

Proc. Natl. Acad. Sci. U.S.A.

105

104

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The axon initial segment (AIS) is a structure at the start of the axon with a high density of sodium and potassium channels that defines the site of action potential generation. It has recently been shown that this structure is plastic and can change its position along the axon, as well as its length, in a homeostatic manner. Chronic activitydeprivation paradigms in a chick auditory nucleus lead to a lengthening of the AIS and an increase in neuronal excitability. On the other hand, a long-term increase in activity in dissociated rat hippocampal neurons results in an outward movement of the AIS and a decrease in the cell's excitability. Here, we investigated whether the AIS is capable of undergoing structural plasticity in rat hippocampal organotypic slices, which retain the diversity of neuronal cell types present at postnatal ages, including chandelier cells. These interneurons exclusively target the AIS of pyramidal neurons and form rows of presynaptic boutons along them. Stimulating individual CA1 pyramidal neurons that express channelrhodopsin-2 for 48 h leads to an outward shift of the AIS. Intriguingly, both the pre-and postsynaptic components of the axo-axonic synapses did not change position after AIS relocation. We used computational modeling to explore the functional consequences of this partial mismatch and found that it allows the GABAergic synapses to strongly oppose action potential generation, and thus downregulate pyramidal cell excitability. We propose that this spatial arrangement is the optimal configuration for a homeostatic response to long-term stimulation.axon initial segment | chandelier cells | optogenetics | intrinsic plasticity | homeostatic plasticity N eurons receive a large number of synaptic inputs along the somato-dendritic compartment that integrate at the axon initial segment (AIS) to fire an action potential (AP) (1-3). As an important site for transforming graded synaptic inputs into all-or-none APs, it is also a potentially sensitive target for the modulation of neuronal excitability (4, 5). In fact, one interesting aspect of principal neurons in the hippocampus and cortex is the presence of a unique type of GABAergic axo-axonic synapse that forms onto the AIS and controls neuronal output (6, 7). These synapses are formed by a specific group of fast-spiking interneurons, the chandelier cells, that are generally found sparsely distributed in the brain and have therefore been difficult to study in the past (6, 8). However, the recently developed transgenic mouse lines that can label chandelier neurons more selectively have begun to shine light on their form and function (9). In the cortex, the axonal "cartridges" of synaptic boutons that form onto the AIS are generally found on the more distal AIS domain, where the AP is thought to initiate (9). Although there is little information on the role of these interneurons in network function, they have been implicated in a number of events, including driving negative feedback in the dentate gyrus (10), modulating the emergence of sha...

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Dentate Gyrus Local Circuit is Implicated in Learning Under Stress—a Role for Neurofascin

Cited by 11 publications

References 26 publications

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output

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