Enhanced long term microcircuit plasticity in the valproic acid animal model of autism

Silva, Guilherme Testa; Bé, Jean-Vincent Le; Riachi, Imad; Markram, Kamila; Markram, Henry

doi:10.3389/neuro.19.001.2009

Cited by 25 publications

(29 citation statements)

References 68 publications

(92 reference statements)

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“…to GW 23–26 in humans), even before thalamocortical synapses are established and before the critical period for thalamocortical plasticity in A1 (Barkat et al, 2011). Our findings are also consistent with general excitatory hyperconnectivity in other cell types and brain regions at older ages in the VPA model (Markram et al, 2007; Rinaldi et al, 2008a; Rinaldi et al, 2008b; Silva et al, 2009). However, the LSPS technique that we employed allowed us to investigate circuit structure on the ‘mesoscale’ (~100 μm), and sample a larger area (~1 mm 2 ) than previous studies.…”

Section: Discussionsupporting

confidence: 87%

“…1A–B). In utero exposure to VPA has been associated with hyperconnectivity in different cortical areas (Markram et al, 2007; Rinaldi et al, 2008a; Rinaldi et al, 2008b; Silva et al, 2009). To test if SPNs received increased excitatory input we performed whole-cell patch recordings of miniature excitatory post-synaptic potentials (mEPSCs) from A1 SPNs in acute TC slices.…”

Section: Resultsmentioning

confidence: 99%

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Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

et al. 2017

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Summary Autism Spectrum Disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as ‘patches’ of mostly increased connection probability or strength in the first postnatal week, and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits, and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as possible common pathophysiological substrate of deficits in ASD.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

et al. 2017

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“…However, STDP does mold synaptic weights (47), and long-term microcircuit plasticity (LTMP) does mold the connectivity between these pyramidal neurons (45,66) in this same preparation. The specific neurons involved in a group may, therefore, be selected by experience, but because of the powerful connectivity constraints that we found, these forms of plasticity is likely to add only minor variations to functioning of neuronal groups.…”

Section: Discussionmentioning

confidence: 99%

A synaptic organizing principle for cortical neuronal groups

Perin

Berger

Markram

2011

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

668

819

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Neuronal circuitry is often considered a clean slate that can be dynamically and arbitrarily molded by experience. However, when we investigated synaptic connectivity in groups of pyramidal neurons in the neocortex, we found that both connectivity and synaptic weights were surprisingly predictable. Synaptic weights follow very closely the number of connections in a group of neurons, saturating after only 20% of possible connections are formed between neurons in a group. When we examined the network topology of connectivity between neurons, we found that the neurons cluster into small world networks that are not scale-free, with less than 2 degrees of separation. We found a simple clustering rule where connectivity is directly proportional to the number of common neighbors, which accounts for these small world networks and accurately predicts the connection probability between any two neurons. This pyramidal neuron network clusters into multiple groups of a few dozen neurons each. The neurons composing each group are surprisingly distributed, typically more than 100 μm apart, allowing for multiple groups to be interlaced in the same space. In summary, we discovered a synaptic organizing principle that groups neurons in a manner that is common across animals and hence, independent of individual experiences. We speculate that these elementary neuronal groups are prescribed Lego-like building blocks of perception and that acquired memory relies more on combining these elementary assemblies into higher-order constructs.cell assemblies | Edelman | Hebb | brain development | learning H ebb's (1) contributions to the theory of learning and memory have shaped psychological, philosophical, and neuroscientific theories for over 60 y. Three of the concepts that he put forward were particularly important. The first defines a correlation-based learning rule, namely that when one neuron persistently drives another, then the connection between them will be strengthened. The second states that this leads to the formation of clustered synaptic coupling of neurons into cell assemblies whose network topologies are molded by experience; the third suggests that such elementary cell assemblies are synaptically linked by the same learning rule to form trains of percepts (a phase sequence), constituting thoughts (1-6). There is a vast body of evidence for all three concepts (5, 7-10).Despite this evidence, theorists have pointed out that the first postulate would cause synapses within cell assemblies to saturate, restricting their dynamic range and limiting memory storage capacity (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Experimental studies have confirmed that saturated long-term potentiation (LTP) is unfavorable to learning and memory (21,22). Although Hebb (1) had suggested a mechanism for passive weakening of unused synaptic connections, these objections suggested the need for an active depressive mechanism (16,17,23), inspiring the discoveries of long-term depression (LTD) (24) and bidirectional and spike timing-dependent plastici...

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“…Studies in our lab demonstrated that the neocortex and amygdala of VPA-treated rat offspring is hyper-reactive and hyper-plastic due to hyper-connectivity between neurons (Rinaldi et al, 2007; Markram et al, 2008; Rinaldi et al, 2008a,b; Silva et al, 2009). These observations indicate excessive processing and storage of information in these nervous systems.…”

Section: Introductionmentioning

confidence: 97%

General developmental health in the VPA-rat model of autism

Favre¹,

Barkat²,

LaMendola³

et al. 2013

Front. Behav. Neurosci.

104

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Autism is a neurodevelopmental condition diagnosed by impaired social interaction, abnormal communication and, stereotyped behaviors. While post-mortem and imaging studies have provided good insights into the neurobiological symptomology of autism, animal models can be used to study the neuroanatomical, neurophysiological and molecular mediators in more detail and in a more controlled environment. The valproic acid (VPA) rat model is an environmentally triggered model with strong construct and clinical validity. It is based on VPA teratogenicity in humans, where mothers who are medicated with VPA during early pregnancy show an increased risk for giving birth to an autistic child. In rats, early embryonic exposure, around the time of neural tube closure, leads to autism-like anatomical and behavioral abnormalities in the offspring. Considering the increasing use of the VPA rat model, we present our observations of the general health of Wistar dams treated with a single intraperitoneal injection of 500 or, 600 mg/kg VPA on embryonic day E12.5, as well as their male and female offspring, in comparison to saline-exposed controls. We report increased rates of complete fetal reabsorption after both VPA doses. VPA 500 mg/kg showed no effect on dam body weight during pregnancy or, on litter size. Offspring exposed to VPA 500 mg/kg showed smaller brain mass on postnatal days 1 (P1) and 14 (P14), in addition to abnormal nest seeking behavior at P10 in the olfactory discrimination test, relative to controls. We also report increased rates of physical malformations in the offspring, rare occurrences of chromodacryorrhea and, developmentally similar body mass gain. Further documentation of developmental health may guide sub-grouping of individuals in a way to better predict core symptom severity.

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Enhanced long term microcircuit plasticity in the valproic acid animal model of autism

Cited by 25 publications

References 68 publications

Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder

A synaptic organizing principle for cortical neuronal groups

General developmental health in the VPA-rat model of autism

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