Kamila Markram

Ecole Polytechnique Federale de Lausanne, Brain Mind Institute, Faculty Member

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Kamila Markram graduated in psychology from the Technical University Berlin in 2003. She did her diploma thesis work at the Max-Planck Institute for Brain Research in Frankfurt focusing on fast coherent responses to visual inputs as a function of prior synchronization states in the visual cortex. She obtained her PhD degree in Neuroscience at the Brain Mind Institute at the Swiss Federal Institute of Technology in Lausanne (EPFL) in 2006, where her work in the Laboratory of Behavioral Genetics was focused on molecular alterations involved in emotional learning and characterization of a rat model of autism. She then joined the Laboratory of Neural Ensemble Physiology at the BMI, EPFL as a post-doc where she continued working on autism using parallel multi-electrode, multi-site recordings in a rat model to unravel the brain circuit alterations underlying autism. Since 2008 she is the autism project group leader in the Laboratory of Neural Microcircuits, BMI, EPFL. This team studies autism in several rodent models using a spectrum of non-invasive and invasive approaches at the genetic, molecular, cellular, synaptic, local circuit, circuit, systems and behavioral level.

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Papers by Kamila Markram

Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood

The neural cell adhesion molecule (NCAM) has been implicated in regulating synaptic plasticity me... more The neural cell adhesion molecule (NCAM) has been implicated in regulating synaptic plasticity mechanisms as well as memory consolidation processes. Attachment of polysialic acid to NCAM (PSA-NCAM) has been reported to down-regulate its adhesive forces, a process hypothesized to be implicated in synapse selection after learning experiences. PSA-NCAM has been critically implicated in hippocampus-related synaptic plasticity and memory storage, but information about its functional role in other brain areas remains scarce.

Hyper-fear, reduced fear extinction and weakened inhibition in the amygdala in an animal model of autism

Text Autism is characterized by inhibited reciprocal social interactions and marked inflexibility... more Text Autism is characterized by inhibited reciprocal social interactions and marked inflexibility to environmental changes, which make rehabilitation exceedingly difficult. Kanner's (1943) and more recent studies suggest that abnormal anxiety and fear processing are also common features in this disorder. A recent model of autism, in which the developing embryo is exposed to valproic acid (VPA) on day 12.5 of gestation, has many anatomical, pathological, etiological and behavioural similarities with human autism.

Hyper-connectivity and hyper-plasticity in the medial prefrontal cortex in the valproic acid animal model of autism

Frontiers in Neural Circuits, Jan 1, 2008

The prefrontal cortex has been extensively implicated in autism to explain deficits in executive ... more The prefrontal cortex has been extensively implicated in autism to explain deficits in executive and other higher-order functions related to cognition, language, sociability and emotion. The possible changes at the level of the neuronal microcircuit are however not known. We studied microcircuit alterations in the prefrontal cortex in the valproic acid rat model of autism and found that the layer 5 pyramidal neurons are connected to significantly more neighbouring neurons than in controls. These excitatory connections are more plastic displaying enhanced long-term potentiation of the strength of synapses. The microcircuit alterations found in the prefrontal cortex are therefore similar to the alterations previously found in the somatosensory cortex. Hyper-connectivity and hyper-plasticity in the prefrontal cortex implies hyper-functionality of one of the highest order processing regions in the brain, and stands in contrast to the hypo-functionality that is normally proposed in this region to explain some of the autistic symptoms. We propose that a number of deficits in autism such as sociability, attention, multi-tasking and repetitive behaviours, should be re-interpreted in the light of a hyper-functional prefrontal cortex.

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The Intense World Theory – a unifying theory of the neurobiology of autism

Autism covers a wide spectrum of disorders for which there are many views, hypotheses and theorie... more Autism covers a wide spectrum of disorders for which there are many views, hypotheses and theories. Here we propose a unifying theory of autism, the Intense World Theory. The proposed neuropathology is hyper-functioning of local neural microcircuits, best characterized by hyper-reactivity and hyper-plasticity. Such hyper-functional microcircuits are speculated to become autonomous and memory trapped leading to the core cognitive consequences of hyper-perception, hyper-attention, hyper-memory and hyper-emotionality. The theory is centered on the neocortex and the amygdala, but could potentially be applied to all brain regions. The severity on each axis depends on the severity of the molecular syndrome expressed in different brain regions, which could uniquely shape the repertoire of symptoms of an autistic child. The progression of the disorder is proposed to be driven by overly strong reactions to experiences that drive the brain to a hyper-preference and overly selective state, which becomes more extreme with each new experience and may be particularly accelerated by emotionally charged experiences and trauma. This may lead to obsessively detailed information processing of fragments of the world and an involuntarily and systematic decoupling of the autist from what becomes a painfully intense world. The autistic is proposed to become trapped in a limited, but highly secure internal world with minimal extremes and surprises. We present the key studies that support this theory of autism, show how this theory can better explain past findings, and how it could resolve apparently conflicting data and interpretations. The theory also makes further predictions from the molecular to the behavioral levels, provides a treatment strategy and presents its own falsifying hypothesis.

The Intense World Syndrome – an alternative hypothesis for autism

Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems ... more Autism is a devastating neurodevelopmental disorder with a polygenetic predisposition that seems to be triggered by multiple environmental factors during embryonic and/or early postnatal life. While significant advances have been made in identifying the neuronal structures and cells affected, a unifying theory that could explain the manifold autistic symptoms has still not emerged. Based on recent synaptic, cellular, molecular, microcircuit, and behavioral results obtained with the valproic acid (VPA) rat model of autism, we propose here a unifying hypothesis where the core pathology of the autistic brain is hyper-reactivity and hyper-plasticity of local neuronal circuits. Such excessive neuronal processing in circumscribed circuits is suggested to lead to hyper-perception, hyper-attention, and hyper-memory, which may lie at the heart of most autistic symptoms. In this view, the autistic spectrum are disorders of hyper-functionality, which turns debilitating, as opposed to disorders of hypo-functionality, as is often assumed. We discuss how excessive neuronal processing may render the world painfully intense when the neocortex is affected and even aversive when the amygdala is affected, leading to social and environmental withdrawal. Excessive neuronal learning is also hypothesized to rapidly lock down the individual into a small repertoire of secure behavioral routines that are obsessively repeated. We further discuss the key autistic neuropathologies and several of the main theories of autism and re-interpret them in the light of the hypothesized Intense World Syndrome.

Enhanced Long Term Microcircuit Plasticity In the Valproic Acid Animal Model of Autism

Front. Syn. …, Jan 1, 2009

A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant... more A single intra-peritoneal injection of valproic acid (VPA) on embryonic day (ED) 11.5 to pregnant rats has been shown to produce severe autistic-like symptoms in the offspring. Previous studies showed that the microcircuitry is hyperreactive due to hyperconnectivity of glutamatergic synapses and hyperplastic due to over-expression of NMDA receptors. These changes were restricted to the dimensions of a minicolumn (<50 μm). In the present study, we explored whether Long Term Microcircuit Plasticity (LTMP) was altered in this animal model. We performed multi-neuron patch-clamp recordings on clusters of layer 5 pyramidal cells in somatosensory cortex brain slices (PN 12–15), mapped the connectivity and characterized the synaptic properties for connected neurons. Pipettes were then withdrawn and the slice was perfused with 100 μM sodium glutamate in artificial cerebrospinal fluid in the recording chamber for 12 h. When we re-patched the same cluster of neurons, we found enhanced LTMP only at inter-somatic distances beyond minicolumnar dimensions. These data suggest that hyperconnectivity is already near its peak within the dimensions of the minicolumn in the treated animals and that LTMP, which is normally restricted to within a minicolumn, spills over to drive hyperconnectivity across the dimensions of a minicolumn. This study provides further evidence to support the notion that the neocortex is highly plastic in response to new experiences in this animal model of autism.

Abnormal Fear Conditioning and Amygdala Processing In An Animal Model of Autism

…, Jan 1, 2007

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Role of NCAM In Emotion and Learning

… and Function of the Neural Cell …, Jan 1, 2010

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Amygdala Upregulation of NCAM Polysialylation Induced by Auditory Fear Conditioning is Not Required for Memory Formation, but Plays a Role In Fear Extinction

Neurobiology of learning …, Jan 1, 2007

There is much interest to understand the mechanisms leading to the establishment, maintenance, an... more There is much interest to understand the mechanisms leading to the establishment, maintenance, and extinction of fear memories. The amygdala has been critically involved in the processing of fear memories and a number of molecular changes have been implicated in this brain region in relation to fear learning. Although neural cell adhesion molecules (NCAMs) have been hypothesized to play a role, information available about their contribution to fear memories is scarce. We investigate here whether polysialylated NCAM (PSA-NCAM) contributes to auditory fear conditioning in the amygdala. First, PSA-NCAM expression was evaluated in different amygdala nuclei after auditory fear conditioning at two different shock intensities. Results showed that PSA-NCAM expression was increased 24 h post-training only in animals subjected to the highest shock intensity (1mA). Second, PSA-NCAM was cleaved in the basolateral amygdaloid complex through micro-infusions of the enzyme endoneuraminidase N, and the consequences of such treatment were investigated on the acquisition, consolidation, remote memory expression, and extinction of conditioned fear memories. Intra-amygdaloid cleavage of PSA-NCAM did not affect acquisition, consolidation or expression of remote fear memories. However, intra-amygdaloid PSA-NCAM cleavage enhanced fear extinction processes. These results suggest that upregulation of PSA-NCAM is a correlate of fear conditioning that is not necessary for the establishment of fear memory in the amygdala, but participates in mechanisms precluding fear extinction. These findings point out PSA-NCAM as a potential target for the treatment of psychopathologies that involve impairment in fear extinction.