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.

To elucidate molecular mechanisms underlying activity-dependent synaptic remodeling in the developing mammalian visual system, we screened for genes whose expression in the lateral geniculate nucleus (LGN) is regulated by spontaneously generated action potentials present prior to vision. Activity blockade did not alter expression in the LGN of 32 known genes. Differential mRNA display, however, revealed a decrease in mRNAs encoding class I major histocompatibility complex antigens (class I MHC). Postnatally, visually driven activity can regulate class I MHC in the LGN during the final remodeling of retinal ganglion cell axon terminals. Moreover, in the mature hippocampus, class I MHC mRNA levels are increased by kainic acid-induced seizures. Normal expression of class I MHC mRNA is correlated with times and regions of synaptic plasticity, and immunohistochemistry confirms that class I MHC is present in specific subsets of CNS neurons. Finally, beta2-microglobulin, a cosubunit of class I MHC, and CD3zeta, a component of a receptor complex for class I MHC, are also expressed by CNS neurons. These observations indicate that class I MHC molecules, classically thought to mediate cell-cell interactions exclusively in immune function, may play a novel role in neuronal signaling and activity-dependent changes in synaptic connectivity.

The alternatively spliced exon EIIIB is regulated in a cell type-specific manner in the rat fibronectin gene. Splicing of EIIIB into fibronectin mRNA is dependent on sequences in the intron immediately downstream of EIIIB. We show that a short, highly repeated TGCATG motif in this intron is important for cell type-specific recognition of EIIIB as an exon. This motif enhances usage of the EIIIB 5' splice site; furthermore, this repeated TGCATG sequence can activate an alternatively spliced exon in the unrelated rat preprotachykinin pre-mRNA. Interestingly, this sequence can also be found within cis-acting elements identified previously in other alternatively spliced genes. This short repeated TGCATG motif is therefore a cell type-specific element that, in addition to controlling fibronectin alternative splicing, may participate in the regulation of other alternative RNA processing events.

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