Lisa M. Boulanger

Autism and Abnormal Development of Brain Connectivity

It has been said that people with autism suffer from a lack of “central coherence,” the cognitive ability to bind together a jumble of separate features into a single, coherent object or concept ([Frith, 1989][1]). Ironically, the same can be said of the field of autism research, which all too

Immune Proteins in Brain Development and Synaptic Plasticity

Many proteins first identified in the immune system are also expressed in the developing and adult nervous system. Unexpectedly, recent studies reveal that a number of these proteins, in addition to their immunological roles, are essential for the establishment, function, and modification of synaptic connections. These include proinflammatory cytokines (e.g., TNFalpha, IL-6), proteins of the innate immune system (e.g., complement C1q and C3, pentraxins, Dscam), members of the major histocompatibility complex class I (MHCI) family, and MHCI-binding immunoreceptors and their components (e.g., PIRB, Ly49, DAP12, CD3zeta). Understanding how these proteins function in neurons will clarify the molecular basis of fundamental events in brain development and plasticity and may add a new dimension to our understanding of neural-immune interactions in health and disease.

Autism as a disorder of neural information processing: Directions for research and targets for therapy.

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

Immune signalling in neural development, synaptic plasticity and disease

Research has long supported the view that the brain is immunologically privileged, in part because normal, uninfected neurons were not thought to express major histocompatibility complex (MHC) class I molecules. Recently, however, it has been shown that neurons normally express MHC class I molecules in vivo. Furthermore, accumulating evidence indicates that neuronal MHC class I does not simply function in an immune capacity, but is also crucial for normal brain development, neuronal differentiation, synaptic plasticity and even behaviour. These findings point to new directions for research, and imply that immune proteins could be involved in the origin and expression of neurological disorders.

Presynaptic depolarization facilitates neurotrophin-induced synapticpotentiation

Neurotrophins have been proposed to participate in activity-dependent modifications of neuronal connectivity and synaptic efficacy. Preferential strengthening of active inputs requires restriction of putative neurotrophin-mediated synaptic potentiation to active synapses. Here we report that potentiation of synaptic efficacy by brain-derived neurotrophic factor (BDNF) is greatly facilitated by presynaptic depolarization at developing neuromuscular synapses. Brief depolarization in the presence of low-level BDNF results in a marked potentiation of both evoked and spontaneous synaptic transmission, whereas exposure to either BDNF or depolarization alone is without effect. This potentiation depends on the relative timing of depolarization and reflects an enhancement of transmitter secretion from the presynaptic neuron. Thus synapses made by active inputs may be selectively strengthened by secreted neurotrophins as part of activity-dependent refinement of developing connections or of mature synapses.

Neuronal plasticity and cellular immunity: shared molecular mechanisms

It is becoming evident that neurons express an unusual number of molecules that were originally thought to be specific to immune functions. One such molecule, class I major histocompatibility complex, is required in the activity-dependent refinement and plasticity of connections in the developing and adult central nervous system, demonstrating that molecules can perform critical roles in both systems. Recent studies reveal striking parallels between cellular signaling mechanisms in the immune and nervous systems that may provide unexpected insights into the development, function, and diseases of both systems.

MHC class I modulates NMDA receptor function and AMPA receptor trafficking.

Proteins of the major histocompatibility complex class I (MHCI) are known for their role in immunity and have recently been implicated in long-term plasticity of excitatory synaptic transmission. However, the mechanisms by which MHCI influences synaptic plasticity remain unknown. Here we show that endogenous MHCI regulates synaptic responses mediated by NMDA-type glutamate receptors (NMDARs) in the mammalian central nervous system (CNS). The AMPA/NMDA ratio is decreased at MHCI-deficient hippocampal synapses, reflecting an increase in NMDAR-mediated currents. This enhanced NMDAR response is not associated with changes in the levels, subunit composition, or gross subcellular distribution of NMDARs. Increased NMDAR-mediated currents in MHCI-deficient neurons are associated with characteristic changes in AMPA receptor trafficking in response to NMDAR activation. Thus, endogenous MHCI tonically inhibits NMDAR function and controls downstream NMDAR-induced AMPA receptor trafficking during the expression of plasticity.

Synapse Remodeling, Compliments of the Complement System

A growing body of evidence indicates that some proteins known for their immune functions also have distinct nonimmune functions in the normal uninjured central nervous system. In this issue, Stevens et al. (2007) demonstrate an unexpected requirement for molecules of the complement cascade in the remodeling of synaptic connections in the developing visual system.

Role of immune molecules in the establishment and plasticity of glutamatergic synapses

An increasing number of studies support an unexpected role for immune molecules in regulating healthy brain functions during development and in adulthood. Here we review the roles of specific immune molecules (including cytokines, components of the complement cascade, and members of the major histocompatibility complex class I family and their receptors) in the formation and plasticity of glutamatergic synapses. These findings add a new dimension to our understanding of neural–immune interactions, and suggest novel molecular mechanisms that may underlie the modification of glutamatergic synapses in both normal and pathological states.

MHC class I immune proteins are critical for hippocampus-dependent memory and gate NMDAR-dependent hippocampal long-term depression

Memory impairment is a common feature of conditions that involve changes in inflammatory signaling in the brain, including traumatic brain injury, infection, neurodegenerative disorders, and normal aging. However, the causal importance of inflammatory mediators in cognitive impairments in these conditions remains unclear. Here we show that specific immune proteins, members of the major histocompatibility complex class I (MHC class I), are essential for normal hippocampus-dependent memory, and are specifically required for NMDAR-dependent forms of long-term depression (LTD) in the healthy adult hippocampus. In β2m(-/-)TAP(-/-)mice, which lack stable cell-surface expression of most MHC class I proteins, NMDAR-dependent LTD in area CA1 of adult hippocampus is abolished, while NMDAR-independent forms of potentiation, facilitation, and depression are unaffected. Altered NMDAR-dependent synaptic plasticity in the hippocampus of β2m(-/-)TAP(-/-)mice is accompanied by pervasive deficits in hippocampus-dependent memory, including contextual fear memory, object recognition memory, and social recognition memory. Thus normal MHC class I expression is essential for NMDAR-dependent hippocampal synaptic depression and hippocampus-dependent memory. These results suggest that changes in MHC class I expression could be an unexpected cause of disrupted synaptic plasticity and cognitive deficits in the aging, damaged, and diseased brain.