Nonsyndromic Xlinked Mental Retardation

There are a variety of different forms of mental retardation that are not "syndromic," or linked to a specific and consistent spectrum of clinical features other than cognitive impairment, and there have been a number of different genes identified as contributing to these nonsyndromic forms of mental retardation. Some of the interesting genes on the X chromosome that have been associated with mental retardation include the L1 neural cell adhesion molecule and three different genes involved in the rho signal transduction cascade (28-31). Rho stands for ras homologue, which like ras is a low-molecular-weight G protein linked to a variety of downstream targets (see figure and reference 32). While the details of the molecular components of this cascade in neurons are still being worked out, three different members of this general cascade have been identified as loci for mental retardation. These include the rho target PAK3 (p21-activated kinase; 31, 33) and the rho guanine nucleotide exchange factors ARHGEF6 (30) and oligophrenin 1 (OPHN1, 34). In general, the

rho cascades control cytoskeleton arrangement, cell migration, and gene expression. Current working models for the rho cascade-associated mental retardation, as well as the retardation associated with L1 protein deficiency, hypothesize the involvement of derangements of cell migration and neuronal process extension.

time-dependent. Fmr2 knockout mice displayed significantly less conditioned fear in the 24-hour delay context test; however, levels of contextual fear conditioning were similar between Fmr2-deficient and wild-type control mice when the test occurred 30 minutes after training. These findings indicate that the Fmr2-deficient mice learn to associate the shock with the training context and can remember the context over a short delay interval, but that these same mice have impaired conditioned fear that is delay-dependent. Overall, these data indicate that the FMR2 protein may play a role in the memory consolidation process for contextual memory.

Ironically, long-term potentiation in area CA1 was found to be enhanced in hippocampal slices of Fmr2 knockout compared to their wild-type littermates (see Figure 9). Thus, this knockout is an example of an animal model of human mental retardation with impaired learning and memory performance and increased LTP, as we discussed in Chapter 9. These findings highlight the importance of keeping

FIGURE 9 Enhanced LTP in Fmr2 knockout mice. (A) Fmr2 knockout hippocampal slices showed enhanced LTP compared with wild-types after a modest LTP-inducing protocol consisting of a single set of tetani while maintaining slices at 25°C [60 minutes after tetanus: n (KO, male) = 9, 167 ± 9%; n (WT, male) = 14, 132 ± 6%; p = .003]. (B) Enhanced LTP in Fmr2 knockout hippocampal slices is present after a single set of tetanic stimulation while maintaining slices at 32°C [60 minutes after tetanus: n (KO, male) = 6, 170 ± 11%; n (WT, male) = 6, 150 ± 5%; p = .14]. (C) Fmr2 knockout mice maintain the enhanced LTP after three sets of HFS at 32°C [60 minutes after tetanus: n (KO, male) = 7, 244 ± 18%; n (WT, male) = 5, 189 ± 20%; p = .020]. (D) In the presence of the NMDA receptor antagonist AP-5 (50 pM), Fmr2 knockout mice showed enhanced NMDA-independent LTP compared with wild types after three trains of 200-Hz stimulation for 1 second separated by 4 minutes at 32°C [60 minutes after tetanus: n (KO, male) = 6, 155 ± 8%; n (WT, male) = 6, 135 ± 4%; p = .038]. Reproduced from Gu et al. (41).

FIGURE 9 Enhanced LTP in Fmr2 knockout mice. (A) Fmr2 knockout hippocampal slices showed enhanced LTP compared with wild-types after a modest LTP-inducing protocol consisting of a single set of tetani while maintaining slices at 25°C [60 minutes after tetanus: n (KO, male) = 9, 167 ± 9%; n (WT, male) = 14, 132 ± 6%; p = .003]. (B) Enhanced LTP in Fmr2 knockout hippocampal slices is present after a single set of tetanic stimulation while maintaining slices at 32°C [60 minutes after tetanus: n (KO, male) = 6, 170 ± 11%; n (WT, male) = 6, 150 ± 5%; p = .14]. (C) Fmr2 knockout mice maintain the enhanced LTP after three sets of HFS at 32°C [60 minutes after tetanus: n (KO, male) = 7, 244 ± 18%; n (WT, male) = 5, 189 ± 20%; p = .020]. (D) In the presence of the NMDA receptor antagonist AP-5 (50 pM), Fmr2 knockout mice showed enhanced NMDA-independent LTP compared with wild types after three trains of 200-Hz stimulation for 1 second separated by 4 minutes at 32°C [60 minutes after tetanus: n (KO, male) = 6, 155 ± 8%; n (WT, male) = 6, 135 ± 4%; p = .038]. Reproduced from Gu et al. (41).

in mind that increases in LTP may be a fundamental mechanism that leads to impaired cognitive processing, just like loss of LTP.

It is interesting to speculate and consider what the role of the FMR2 protein, a presumed transcriptional regulator, may be doing in LTP and memory. As shown in Figure 9, FMR2 appears to somehow control a "ceiling" for the maximum amount of LTP that can be induced—loss of FMR2 leads to an increased maximum poten-tiation. It is intriguing to consider that transcriptional regulation by FMR2 might somehow be involved in limiting the overall amount of potentiation that can be achieved, although this idea is, of course, highly speculative.

Regardless, the mechanism of enhanced LTP in Fmr2 knockout mice is not clear at this moment. The studies of Wu et al. indicate that the enhancement of LTP in Fmr2 knockout mice is not entirely dependent on NMDA receptor-dependent processes, as NMDA receptor-independent LTP was also augmented (see Figure 9). Most mice with abnormal LTP have been created by knockout of postsynaptic receptors, scaffolding proteins, or protein kinases, while FMR2 is a nuclear protein, a member of a new family of putative transcription factors. It will be interesting in the future to begin to parse out more directly the role of the FMR2 protein in controlling synaptic plasticity.

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