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Loss-of-function mutations or abnormal expression of the X-linked gene encoding methyl CpG binding protein 2 (MeCP2) cause a spectrum of postnatal neurodevelopmental disorders including Rett syndrome (RTT), nonsyndromic mental retardation, learning disability, and autism. Mice expressing a truncated allele of Mecp2 (Mecp2 308 ) reproduce the motor and social behavior abnormalities of RTT; however, it is not known whether learning deficits are present in these animals. We investigated learning and memory, neuronal morphology, and synaptic function in Mecp2 308 mice. Hippocampus-dependent spatial memory, contextual fear memory, and social memory were significantly impaired in Mecp2 308 mutant males (Mecp2 308/Y ). The morphology of dendritic arborizations, the biochemical composition of synaptosomes and postsynaptic densities, and brain-derived neurotrophic factor expression were not altered in these mice. However, reduced postsynaptic density cross-sectional length was identified in asymmetric synapses of area CA1 of the hippocampus. In the hippocampus of symptomatic Mecp2 308/Y mice, Schaffer-collateral synapses exhibited enhanced basal synaptic transmission and decreased paired-pulse facilitation, suggesting that neurotransmitter release was enhanced. Schaffer-collateral long-term potentiation (LTP) was impaired. LTP was also reduced in the motor and sensory regions of the neocortex. Finally, very early symptomatic Mecp2 308/Y mice had increased basal synaptic transmission and deficits in the induction of long-term depression. These data demonstrate a requirement for MeCP2 in learning and memory and suggest that functional and ultrastructural synaptic dysfunction is an early event in the pathogenesis of RTT.

To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse, we targeted 154 CAG repeats into the endogenous mouse locus. Sca1(154Q/2Q) mice developed a progressive neurological disorder that resembles human SCA1, featuring motor incoordination, cognitive deficits, wasting, and premature death, accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region, being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells, the most affected in SCA1, did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.

For some time I have been involved in efforts to develop computer-controlled systems for instruction. One such effort has been a computer-assistedinstruction (CAI) program for teaching reading in the primary grades (Atkinson, 1974) and another for teaching computer science at the college level (Atkinson, in press). The goal has been to use psychological theory to devise optimal instructional procedures-procedures that make moment-by-moment decisions based on the student's unique response history. To help guide some of the theoretical aspects of this work, research has also been done on the restricted but well-defined problem of optimizing the teaching of a foreign language vocabulary. This is an area in which mathematical models provide an accurate description of learning, and these models can be used in conjunction with the methods of control theory to develop precise algorithms for sequencing instruction among vocabulary items. Some of this work has been published, and those who have read about it know that the optimization schemes are quite effective-far more effective than procedures that permit the learner to make his own instructional decisions (Atkinson, 1972a(Atkinson, , 1972bAtkinson & Paulson, 1972).In conducting these vocabulary learning experiments, I have been struck by the incredible variability in learning rates across subjects. Even Stanford University students, who are a fairly select sample, display impressively large betweensubject differences. These differences may reflect differences in fundamental abilities, but it is easy to demonstrate that they also depend on the strategies that subjects bring to bear on the task. Good learners can introspect with ease about a "bag of tricks" for learning vocabulary items, whereas poor

We targeted 266 CAG repeats (a number that causes infantile-onset disease) into the mouse Sca7 locus to generate an authentic model of spinocerebellar ataxia type 7 (SCA7). These mice reproduced features of infantile SCA7 (ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments. Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however, ataxin-7 staining became more pronounced. Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of nuclear inclusions. These data demonstrate that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).

Describes a theory of human memory in which a distinction is made between 3 memory stores: the sensory register, and the short- and long-term stores. Primary emphasis is given to the processes by which information is stored in and retrieved from the long-term store, a store which is considered to be a permanent repository for information. Forgetting and related phenomena are attributed to a failure of the retrieval process, in which the search through some memory area becomes less efficient as new information is placed in it. Storage and retrieval in the long-term store are conceived of as parallel processes, one mirroring the other, and each is divided into 3 stages for conceptual clarity. The memory trace is viewed as an ensemble of information stored in some memory location, the location of storage determined largely by the components of the ensemble itself. The ability of the system to cope with diverse phenomena is demonstrated by a number of selected experimental paradigms. (2 p. ref.)