Leucine-rich repeat genes and the fine-tuning of synapses.

v e l v l g e s n h e o p F l a t t i C d p P resynaptic neurexins and postsynaptic neuroligins are celladhesion proteins that interact across the synaptic cleft and influence synaptic function (1). These proteins have received recent attention in psychiatry because of genetic evidence linking them to schizophrenia, autism, and mental retardation (1). However, during the last 2 years, an additional family of synaptic adhesion proteins has been found to play a directly cooperative role with the neurexins and neuroligins in glutamate synapse differentiation (2– 4) (Figure 1). This novel gene family is known as the leucine-rich repeat transmembrane neuronal (LRRTM) family, and early evidence is accumulating that these genes are also implicated in psychiatric disease (5– 8). The genetic evidence implicating the neurexins and neuroligins in psychiatry is based particularly on rare and overtly disruptive alterations in humans, such as copy number variants and mutations, as well as on animal models (1). The specific abundances of each neurexin/neuroligin family member or their isoforms that interact at an individual synapse are likely to affect individual synaptic transmission functions and stability (1,9). Thus, the properties of neural networks and systems important for cognition can easily be imagined to depend on the precise functioning of these synaptic organizer/modifier genes. The four-member LRRTM gene family was first described in 2003 (10). The LRRTM proteins have intracellular tails of 71 or 72 amino acids, single transmembrane domains, and 10 extracellular leucinerich repeat (LRR) domains (Figure 1). The LRR domains are involved in protein–protein interactions and are found in a variety of brainenriched, neuronal growth-modulating genes (10). The structures and expression distributions of LRRTMs point to functions in cell surface signaling and/or cell adhesion, particularly within postmitotic neurons of specific regions of the brain (5,10). The LRRTM messenger RNAs are developmentally upregulated in the mouse brain, starting from at least as early as embryonic day 13–15, and reach high levels by postnatal day 1(10). In the adult mouse brain, LRRTM1 and LRRTM2 are both expressed strongly in neurons of the cerebral cortex, striatum, CA1-CA3 pyramidal layers, and the dentate gyrus granular layer of the hippocampus and broadly in the thalamus (as well as in the olfactory bulb) (10). However, although LRRTM1 is expressed in superficial neurons of the cerebral cortex excluding Layer 1, LRRTM2 expression is more prominent in deep layers. Also LRRTM1 is not expressed strongly in the cerebellum, in contrast to LRRTM2. The other family members, LRRTM3 and LRRTM4, also show similarities of expression in the mouse brain, including high expression in the cerebral cortex, with a similar pattern across the layers (i.e., excluding Layer 1; high in Layer 2; lower in Layer 3; and moderate in Layers 4, 5, and 6) (10). Both genes are also expressed highly in the striatum, whereas in the hippocampus high expression of LRRTM3 and LRRTM4 is seen in the dentate gyrus granular layer, but