Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, longterm structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3ζ, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).The development of precise connections in the CNS is critically dependent on neural activity, which drives the elimination of inappropriate connections and the stabilization of appropriate ones. In the visual system of higher mammals, the refinement of initially imprecise axonal connections requires spontaneously generated activity early in development and visually driven activity later (1-4). Fine-tuning of neural connectivity is thought to result from changes in synaptic strength, driven by patterned impulse activity (1,2,5,6).To identify molecules critical for activity-dependent structural remodeling, we previously conducted an unbiased screen for mRNAs selectively regulated by blocking spontaneously generated activity in the developing cat visual system. This manipulation prevents the remodeling of retinal axons from each eye into layers within the lateral geniculate nucleus (LGN) (7-9). Although many known neural genes were not detectably regulated by activity blockade, this screen revealed to our surprise that members of the class I MHC protein family are expressed by neurons and are regulated by spontaneous and evoked neural activity (10). Neuronal class I MHC expression corresponds to well-characterized times and regions of activity-dependent development and plasticity of CNS connections, including retina, LGN, and hippocampus. Furthermore, the mRNA for CD3ζ [a class I MHC receptor subunit in the immune system (11)] is also expressed by neurons (10), consistent with its interaction with class I MHC during activity-dependent remodeling and plasticity. Although class I MHC is primarily known for its function in cell-mediated immune recognition, the above findings from our differential screen suggest that class I MHC molecules may play roles in structural and synaptic remodeling in the developing and mature CNS.

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). Ironically, the same can be said of the field of autism research, which all too often seems a fragmented tapestry stitched from differing analytical threads and theoretical patterns. Defined and diagnosed by purely behavioral criteria, autism was first described and investigated using the tools of behavioral psychology. More recent years have added brain anatomy and physiology, genetics, and biochemistry, but results from these new domains have not been fully integrated with what is known about autistic behavior. The unification of these many levels of analysis will not only provide therapeutic targets for prevention and remediation of autism but can also provide a test case for theories of normal brain and cognitive development. Autism research therefore has much to learn from and much to offer to the broader neuroscience community. Clinical featuresClinically, autism is defined by a "triad" of deficits comprising impaired social interaction, impaired communication, restricted interests, and repetitive behaviors. Although in some cases speech never develops fully or never develops at all, in other cases, speech may be present but so inflexible and unresponsive to context that it is unusable in normally paced conversation; often, speech is limited to echolalia or confined to narrow topics of expertise in which discourse can proceed without conversational interplay. The communicative impairment extends also to nonverbal signals such as gaze, facial expression, and gesture. Social behaviors, too, are beset by a lack of flexibility and rapid coordination: children with autism do not coordinate attention between objects of mutual interest and the other people who may be interested in them, often engage in "parallel play" at the edge of a group rather than joining in cooperative play, and do not engage in pretend play. Intense and narrowly focused interests tend to concentrate on systems (Baron-Cohen, 2002) that operate deterministically and repeatably according to tractable sets of rules, whether these are abstract and complex systems such as computers or roleplaying games or very concrete and simple systems such as toilets or washing machines. Critical to identifying the causal factors of autism, and key to its relevance to normal development, is the recognition that autism is actually the extreme of a spectrum of abnormalities. Milder phenotypes on this spectrum include Asperger syndrome (Wing, 1981) in which language is relatively unimpaired, and the "Broader Autism Phenotype" in which characteristic cognitive traits are present subclinically . The combination of this broad variation of phenotypes and a 60 -90% concordance rate in identical twins suggests a large number of genetic and environmental biasing factors (Muhle et al., 2004). A basis in neural connectivity?In addition to the central coherence par...

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.

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