scholarly journals Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

2021 ◽  
Author(s):  
Shekib Ahmad Jami ◽  
Scott Cameron ◽  
Jonathan M Wong ◽  
Emily R Daly ◽  
A. Kimberly McAllister ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Feedback Inhibition ◽  
Pyramidal Cells ◽  
Serine Racemase ◽  
Inhibitory Synapses ◽  
Gabaergic Neurotransmission ◽  
Gabaergic Synapses ◽  
Genetic Deletion

There is substantial evidence that both NMDA receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. While models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR co-agonist d-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically-driven neuronal excitability without changes in intrinsic excitability. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading to disrupted feedback inhibition and impaired neuronal synchrony.

scholarly journals Increased excitation-inhibition balance due to a loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction

2020 ◽  
Author(s):  
Shekib A. Jami ◽  
Scott Cameron ◽  
Jonathan M. Wong ◽  
Emily R. Daly ◽  
A. Kimberley McAllister ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Pyramidal Neurons ◽  
Feedback Inhibition ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Serine Racemase ◽  
Oscillatory Activity ◽  
Gabaergic Synapse ◽  
Gabaergic Synapses ◽  
Genetic Deletion

AbstractThere is substantial evidence that both NMDA receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. While models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR co-agonist D-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically-driven neuronal excitability and elevated broad-spectrum oscillatory activity in ex vivo hippocampal slices. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapse development leading to disrupted feedback inhibition and impaired neuronal synchrony.

scholarly journals Postsynaptic serine racemase regulates NMDA receptor function

2020 ◽  
Author(s):  
Jonathan M. Wong ◽  
Oluwarotimi Folorunso ◽  
Eden V. Barragan ◽  
Cristina Berciu ◽  
Theresa L. Harvey ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Single Neuron ◽  
Pyramidal Neurons ◽  
Serine Racemase ◽  
Conditional Knockout ◽  
Functional Implications ◽  
Age Dependent ◽  
Nmda Receptor Function ◽  
A Cell ◽  
Genetic Deletion

AbstractD-serine is the primary NMDA receptor (NMDAR) co-agonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic D-serine remains limited. Though early studies suggested D-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and D-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons, as well as the presence of SR in human hippocampal synaptosomes. In addition, using a single-neuron genetic approach in SR conditional knockout mice, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at one month of age. Interestingly, there was a restoration of LTP by two months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of D-serine action.

scholarly journals Premature changes in neuronal excitability account for hippocampal network impairment and autistic-like behavior in neonatal BTBR T+tf/J mice

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Giada Cellot ◽  
Laura Maggi ◽  
Maria Amalia Di Castro ◽  
Myriam Catalano ◽  
Rosanna Migliore ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Single Channel ◽  
Pyramidal Cells ◽  
Inhibitory Effect ◽  
Neuronal Firing ◽  
Gabaergic Neurotransmission ◽  
Principal Cells ◽  
Hippocampal Network ◽  
Ca3 Pyramidal Cells ◽  
Experimental Findings

Abstract Coherent network oscillations (GDPs), generated in the immature hippocampus by the synergistic action of GABA and glutamate, both depolarizing and excitatory, play a key role in the construction of neuronal circuits. In particular, GDPs-associated calcium transients act as coincident detectors for enhancing synaptic efficacy at emerging GABAergic and glutamatergic synapses. Here, we show that, immediately after birth, in the CA3 hippocampal region of the BTBR T+tf/J mouse, an animal model of idiopathic autism, GDPs are severely impaired. This effect was associated with an increased GABAergic neurotransmission and a reduced neuronal excitability. In spite its depolarizing action on CA3 pyramidal cells (in single channel experiments E GABA was positive to E m ), GABA exerted at the network level an inhibitory effect as demonstrated by isoguvacine-induced reduction of neuronal firing. We implemented a computational model in which experimental findings could be interpreted as the result of two competing effects: a reduction of the intrinsic excitability of CA3 principal cells and a reduction of the shunting activity in GABAergic interneurons projecting to principal cells. It is therefore likely that premature changes in neuronal excitability within selective hippocampal circuits of BTBR mice lead to GDPs dysfunction and behavioral deficits reminiscent of those found in autistic patients.

scholarly journals Modeling unitary fields and the single-neuron contribution to local field potentials in the hippocampus

2019 ◽  
Author(s):  
Maria Teleńczuk ◽  
Bartosz Teleńczuk ◽  
Alain Destexhe
Keyword(s):  
Local Field ◽  
Computational Models ◽  
Pyramidal Neurons ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Inhibitory Synapses ◽  
Simple Method ◽  
Hippocampal Pyramidal Neurons

AbstractSynaptic currents represent a major contribution to the local field potential (LFP) in brain tissue, but the respective contribution of excitatory and inhibitory synapses is not known. Here, we provide estimates of this contribution by using computational models of hippocampal pyramidal neurons, constrained by in vitro recordings. We focus on the unitary LFP (uLFP) generated by single neurons in the CA3 region of the hippocampus. We first reproduce experimental results for hippocampal basket cells, and in particular how inhibitory uLFP are distributed within hippocampal layers. Next, we calculate the uLFP generated by pyramidal neurons, using morphologically-reconstructed CA3 pyramidal cells. The model shows that the excitatory uLFP is of small amplitude, smaller than inhibitory uLFPs. Indeed, when the two are simulated together, inhibitory uLFPs mask excitatory uLFPs, which might create the illusion that the inhibitory field is generated by pyramidal cells. These results provide an explanation for the observation that excitatory and inhibitory uLFPs are of the same polarity, in vivo and in vitro. These results also show that somatic inhibitory currents are large contributors of the LFP, which is important information to interpret this signal. Finally, the results of our model might form the basis of a simple method to compute the LFP, which could be applied to point neurons for each cell type, thus providing a simple biologically-grounded method to calculate LFPs from neural networks.

scholarly journals Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output

2019 ◽  
Author(s):  
Matt Udakis ◽  
Victor Pedrosa ◽  
Sophie E.L. Chamberlain ◽  
Claudia Clopath ◽  
Jack R Mellor
Keyword(s):  
Pyramidal Neurons ◽  
Physiological Activity ◽  
Activity Patterns ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Inhibitory Synapses ◽  
Ca1 Pyramidal Cells ◽  
Hippocampal Cell ◽  
Hippocampal Network

SummaryThe formation and maintenance of spatial representations within hippocampal cell assemblies is strongly dictated by patterns of inhibition from diverse interneuron populations. Although it is known that inhibitory synaptic strength is malleable, induction of long-term plasticity at distinct inhibitory synapses and its regulation of hippocampal network activity is not well understood. Here, we show that inhibitory synapses from parvalbumin and somatostatin expressing interneurons undergo long-term depression and potentiation respectively (PV-iLTD and SST-iLTP) during physiological activity patterns. Both forms of plasticity rely on T-type calcium channel activation to confer synapse specificity but otherwise employ distinct mechanisms. Since parvalbumin and somatostatin interneurons preferentially target perisomatic and distal dendritic regions respectively of CA1 pyramidal cells, PV-iLTD and SST-iLTP coordinate a reprioritisation of excitatory inputs from entorhinal cortex and CA3. Furthermore, circuit-level modelling reveals that PV-iLTD and SST-iLTP cooperate to stabilise place cells while facilitating representation of multiple unique environments within the hippocampal network.

scholarly journals Hypoosmolar dose-dependent swelling occurs in both pyramidal neurons and astrocytes in acute hippocampal slices

2017 ◽  
Author(s):  
Thomas R. Murphy ◽  
David Davila ◽  
Nicholas Cuvelier ◽  
Leslie R. Young ◽  
Kelli Lauderdale ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Extracellular Space ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Water Channel ◽  
Pyramidal Cells ◽  
Volume Changes ◽  
Osmotic Swelling ◽  
Neuronal Swelling

AbstractNormal nervous system function is critically dependent on the balance of water and ions in the extracellular space. Pathological reduction in brain interstitial osmolarity results in osmotically-driven flux of water into cells, causing cellular edema which reduces the extracellular space and increases neuronal excitability and risk of seizures. Astrocytes are widely considered to be particularly susceptible to cellular edema due to selective expression of the water channel aquaporin-4 (AQP4). The apparent resistance of pyramidal neurons to osmotic swelling has been attributed to lack of functional water channels. In this study we report rapid volume changes in CA1 pyramidal cells in hypoosmolar ACSF (hACSF) that are equivalent to volume changes in astrocytes across a variety of conditions. Astrocyte and neuronal swelling was significant within 1 minute of exposure to 17 or 40% hACSF, was rapidly reversible upon return to normosmolar ACSF, and repeatable upon re-exposure to hACSF. Neuronal swelling was not an artifact of patch clamp, occurred deep in tissue, was similar at physiological vs. room temperature, and occurred in both juvenile and adult hippocampal slices. Neuronal swelling was neither inhibited by TTX, nor by antagonists of NMDA or AMPA receptors, suggesting that it was not occurring as a result of excitotoxicity. Surprisingly, genetic deletion of AQP4 did not inhibit, but rather augmented, astrocyte swelling in severe hypoosmolar conditions. Taken together, our results indicate that neurons are not osmoresistant as previously reported, and that osmotic swelling is driven by an AQP4-independent mechanism.

Modeling Hippocampal CA1 Gabaergic Synapses of Audiogenic Rats

2020 ◽  
Vol 30 (05) ◽  
pp. 2050022
Author(s):  
Rodrigo F. O. Pena ◽  
Cesar Celis Ceballos ◽  
Júnia Lara De Deus ◽  
Antonio Carlos Roque ◽  
Norberto Garcia-Cairasco ◽  
...  
Keyword(s):  
Computational Model ◽  
Pyramidal Neurons ◽  
Temporal Dynamics ◽  
Pyramidal Cells ◽  
Homogeneous Population ◽  
Ca1 Pyramidal Cells ◽  
Physiological Properties ◽  
Hippocampal Ca1 ◽  
Gabaergic Synapses ◽  
Ca1 Pyramidal Neuron

Wistar Audiogenic Rats (WARs) are genetically susceptible to sound-induced seizures that start in the brainstem and, in response to repetitive stimulation, spread to limbic areas, such as hippocampus. Analysis of the distribution of interevent intervals of GABAergic inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal cells showed a monoexponential trend in Wistar rats, suggestive of a homogeneous population of synapses, but a biexponential trend in WARs. Based on this, we hypothesize that there are two populations of GABAergic synaptic release sites in CA1 pyramidal neurons from WARs. To address this hypothesis, we used a well-established neuronal computational model of a CA1 pyramidal neuron previously developed to replicate physiological properties of these cells. Our simulations replicated the biexponential trend only when we decreased the release frequency of synaptic currents by a factor of six in at least 40% of distal synapses. Our results suggest that almost half of the GABAergic synapses of WARs have a drastically reduced spontaneous release frequency. The computational model was able to reproduce the temporal dynamics of GABAergic inhibition that could underlie susceptibility to the spread of seizures.

scholarly journals Potassium channels contribute to activity-dependent scaling of dendritic inhibition

2017 ◽  
Author(s):  
Jeremy T. Chang ◽  
Michael J. Higley
Keyword(s):  
Potassium Channels ◽  
Neuronal Activity ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Gabaergic Inhibition ◽  
Voltage Gated ◽  
The Impact ◽  
Activity Dependent

AbstractGABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.Significance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

Layer-Specific Generation and Propagation of Seizures in Slices of Developing Neocortex: Role of Excitatory GABAergic Synapses

2008 ◽  
Vol 100 (2) ◽  
pp. 620-628 ◽  
Author(s):  
Sylvain Rheims ◽  
Alfonso Represa ◽  
Yehezkel Ben-Ari ◽  
Yuri Zilberter
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Neonatal Period ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Nmda Channel ◽  
Gabaergic Synapses ◽  
Developing Neocortex ◽  
Excitatory Gaba

The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6–P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential ( Em), we show that transition from IISs to ISs is associated with a gradual Em depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by Em depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

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