Amygdala GluN2B-NMDAR dysfunction is critical in abnormal aggression of neurodevelopmental origin induced by St8sia2 deficiency

Aggression is frequently observed in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Due to a lack of understanding of its underlying mechanisms, effective treatments for abnormal aggression are still missing. Recently, genetic variations in Sialyltransferase 2 (St8sia2) have been linked to these disorders and aggression. Here we identify abnormal aggressive behaviors and concomitant blunted fear learning in St8sia2 knockout (−/−) mice. It is worth noting that the amygdala of St8sia2−/− mice shows diminished threat-induced activation, as well as alterations in synaptic structure and function, including impaired GluN2B-containing NMDA receptor-mediated synaptic transmission and plasticity. Pharmacological rescue of NMDA receptor activity in the amygdala of St8sia2−/− mice with the partial agonist d-cycloserine restores synaptic plasticity and normalizes behavioral aberrations. Pathological aggression and associated traits were recapitulated by specific amygdala neonatal St8sia2 silencing. Our results establish a developmental link between St8sia2 deficiency and a pathological aggression syndrome, specify synaptic targets for therapeutic developments, and highlight d-cycloserine as a plausible treatment.

Altered neocortical microcircuitry in the valproic acid rat model of autism

Tania Rinaldi

Autism is a wide-spectrum disorder with early childhood onset, affecting general cognitive capabilities and, in particular, complex information processing. Although interesting directions of research start to appear, the precise causes of the disorder and the resulting brain alterations have not been elucidated yet. The goal of this research project is to get a better understanding of the neocortical microcircuitry alterations in autism, using the valproic acid (VPA) rat model of autism. Exposure to VPA can cause several teratogenic effects, including autism in human if exposure occurs during the third week of gestation. Previous studies explored the results of prenatal VPA exposure in rats and found similar gross abnormalities to those in autism, such as diminished number of Purkinje cells. Behavioural studies further showed that a number of core symptoms, such as impairment in social interactions and higher sensitivity to sensory stimulation, are also present in the VPA-treated rats. We examined the postnatal effects of embryonic exposure to VPA on the microcircuitry properties of juvenile rat neocortex using in vitro electrophysiology. We found that prenatal VPA injection causes a significant increase of more than 50% of the local connectivity formed by pyramidal neurons of the somatosensory cortex, and that the neocortical network becomes hyper-reactive to external stimuli. We identify two possible compensatory mechanisms that may follow the observed hyperconnectivity: reduced excitability of pyramidal neurons and a decreased magnitude for individual synaptic connections. We also illustrate how NMDA receptors are significantly enhanced in the rat model and how this enhancement is associated with an increased plasticity in the neocortex. Both the somatosensorial and prefrontal cortex exhibit increased plasticity, suggesting a general enhanced plasticity in the brains of VPA-exposed rats. In addition, we show that multi-electrode array stimulation of the lateral amygdala reveals a hyper-reactive amygdala with increased synaptic plasticity. These alterations may account for some of the core symptoms in autism spectrum disorders. For example, hyperconnectivity could underlie symptoms such as aberrant reactions to sensory stimulation and altered attention. Also, the enhancement of NMDA mediated transmission and increased plasticity could explain the unusual learning and memory capabilities of some autistic children. Finally, we propose that the hyper-reactive and hyper-plastic amygdala underlies abnormal fear processing in this animal model of autism. We further speculate that abnormal fear processing could be a core pathology in autism which may give rise to behavioural symptoms, such as impairments in social interactions and resistance to rehabilitation.

EPFL2006

The role of the amygdala in emotional memories

Kamila Markram, Maria del Carmen Sandi Perez

This thesis investigates the role of the amygdala for the establishment of fear memories with a multidisciplinary approach, including behavioural, psychopharmacological, genetic, molecular, and electrophysiological techniques in rats or mice, under healthy or pathological conditions. This research program aims to shed light on the acquisition and storage of emotional memories in the amygdala and closely interconnected brain areas. In one line of experiments, the molecular mechanisms leading to the establishment of fear memory traces in the amygdala were investigated. For this purpose, the functional role of the polysialylated neural cell adhesion molecule PSA-NCAM, expressed in the synaptic junction, was assessed in the amygdala – and also prefrontal cortex and hippocampus – with psychopharmacological and genetic approaches and tasks that strongly rely on these brain areas. Two lines of studies were followed: 1) amygdala-targeted cleavage and enhancement of PSA-NCAM in rats and 2) general cleavage of PSA-NCAM throughout the brain using genetically modified mice. Taken together, both approaches show that amygdaloid PSA-NCAM plays no role in the acquisition and storage of fear memories, but is rather involved in their extinction. Furthermore, the results confirm the importance of PSA-NCAM in hippocampus mediated learning and for the first time show that prefrontal cortex mediated learning depends on PSA-NCAM. These results suggest that PSA-NCAM is selectively involved in some, but not all, synaptic plasticity processes in the brain. In another line of experiments, the valproic acid (VPA) animal model of autism was used to investigate a possible contribution of the amygdala towards the autistic pathology. VPA was injected once at a specific time point during gestation, the time of neural tube closure. The offspring of such treated rats were first characterized in a broad set of behavioural tasks. It was found that VPA-treated offspring exhibited very specific behavioural anomalies closely resembling autistic symptomotology, such as impaired social interaction, exploration and recognition, enhanced repetitive behaviours, impaired sensorimotor gating and increased anxiety, while other behavioural parameters were left unharmed. Once the validity of the model was established, amygdala functionality was assessed. The results demonstrated that VPA-treated offspring exhibited highly enhanced conditioned fear memories, which generalized to other stimuli and were resistant to extinction. Electrophysiological in vitro recordings in the amygdala revealed hyper-reactivity towards stimulation and enhanced activity-induced synaptic plasticity. These results imply that enhanced activity and plasticity in the amygdala may underlie the exaggerated fear memories. Furthermore it is suggested in this thesis that a hyper-reactive amygdala may underlie some of the most basic symptoms observed in autism: reduced social interactions and resistance to rehabilitation.

EPFL2007

Stress-induced cognitive and psychopathological alterations

Reto Bisaz, Maria del Carmen Sandi Perez

Intensive research over the past few years has provided evidence, that stress is a potent modulator of brain function and cognition. In particular cognitive and emotional processes have been shown to be susceptible to modulation by stress. Whereas acute stress and/or a transient activation of the stress system can have beneficial consequences on learning and memory processes, prolonged or extensive stress can induce structural and functional alterations in various brain regions, which are accompanied by cognitive impairments and emotional changes. Moreover, increasing evidence points out that inappropriate stress response and/or control might be associated with the development and exacerbation of a variety of neuropsychiatric disorders. The neural cell adhesion molecule (NCAM), a cell surface macromolecule which is abundantly expressed in the vertebrate nervous system, plays a key role during neural development and has been implicated in activity induced synaptic plasticity as well as cognitive and emotional processes in adulthood. Altered expression of NCAM has been hypothesized to be one of the key events underlying structural and functional alterations in response to stress and accumulating evidence in rodents are showing decreased hippocampal NCAM expression after chronic stress. However, since most of the available evidence for this hypothesis has been either correlational or circumstantial, we aimed here to provide evidence for a causal involvement of NCAM in stress-induced cognitive and emotional disturbances. For this purpose, we evaluated the consequence of 4 weeks of chronic stress in adult wild-type mice on NCAM expression levels in brain regions, known to play a key role in cognition and emotions in a variety of cognitive and emotional tests. We found, that chronically stressed mice have reduced hippocampal NCAM expression levels and display learning and memory impairments, in hippocampus dependent behavioral tasks. Strikingly, similar patterns of cognitive impairments were also found in conditional NCAM-deficient mice, in which the NCAM gene is ablated in the forebrain postnatally. Interestingly, spatial learning and memory impairments of these mice could be recovered by treatments with NCAM mimetic peptides, which are known to potentiate NCAM functioning. Moreover, conditional NCAM-deficient mice displayed increased vulnerability to develop cognitive and emotional disturbances following subchronic stress exposure, a condition which has been shown to induce none (or only slight) structural and behavioral alterations in wild-type rodents. In the amygdala, a brain structure involved in consolidation of emotional memories, NCAM expression was increased in mice exposed to chronic stress. Additionally, chronically stressed mice displayed facilitated auditory fear conditioning, a behavioral task that critically depends on amygdala functions. Contrary, conditional NCAM-deficient mice displayed reduced conditioned auditory fear responses, which indicates a possible involvement of changes in amygdala NCAM expression and altered auditory fear conditioning. Together, the findings of the present study support a functional involvement of alterations in NCAM expression levels in stress-induced cognitive and emotional alterations and highlight this molecule as a potential target for the treatment of stress-related cognitive and emotional disturbances.

EPFL2009