Aging and Cognition

Deficits in learning and memory (L&M) occur with aging, but little is known about what causes them. Recent studies in our laboratory demonstrated that just as humans and other animals, mice show age-related deficits in a variety of learning tests. Interestingly, cells in the brain become progressively less excitable with age, and previous studies suggested that this decrease in excitability could cause deficits in learning and memory. Remarkably, our laboratory has shown that a change in a gene that increases the excitability of brain cells (the Kvb1.1 gene) improves synaptic plasticity (a candidate cellular mechanism for learning and memory) and learning and memory specifically in aged mice.

It is important to note that the cognitive decline associated with aging is unrelated to diseases such as Alzheimer's. The AHP (afterhyperpolarization) of hippocampal CA1 neurons increases with age, presumably due to an elevation in L-type Ca2+ channel density. This molecular change is the principal cause for the age-related decrease in neuronal excitability. In addition, the threshold for the induction of long term potentiation (LTP) at hippocampal CA1 synapses also increases with age as a consequence of the enhanced AHP. LTP is a form of synaptic plasticity thought to be involved in learning and memory.

The enhanced AHP, and the decreased LTP may be responsible for age-associated hippocampus-dependent learning and memory deficits. Accordingly, previous studies showed that manipulations that attenuate L-type Ca2+ channel function have been shown to improve learning in aged rats and rabbits. However, these agents also improve learning in young adult subjects, and therefore it is unclear whether they target the mechanisms responsible for age-related cognitive deficits. To test whether an increase in the AHP contributes to cognitive decline observed in aged animals, we performed experiments with a null mutant for the modulatory potassium channel subunit Kv?.1, which has decreased AHP. Our results indicate that this decrease in the AHP may prevent age-dependent deficits in LTP of synaptic transmission and in learning. The aged mutants show AHP, LTP and learning that is indistinguishable from that of young normal mice.

Neurofribomatosis TypeI

Specific learning disabilities are the most common neurological complication of children with Neurofibromatosis type I (NF1). The inherent complexity of these cognitive deficits, and the complications of pursuing their study in patients, motivated us to study them in mice with the same mutation that in humans causes NF1(Nf1+/- mutants). We have showed that these mice have very specific learning deficits that have striking similarities to the deficits of children with NF1. Our biological studies of mice with NF1 have yielded a treatment for the learning deficits in mice, and we have initiated the complex process of determining whether the same approach can cure the learning deficits of patients with NF1.

Our work showed that Nf1+/- mutants have spatial learning deficits, but not visible-platform deficits, in the Morris water maze. Interestingly, we have recently found that although mice with a heterozygous null mutation of the K-ras gene (K-ras+/-) also showed spatial learning deficits, the K-ras+/- mutation can rescue the spatial learning phenotype of the Nf1+/- mice. Similarly, our work also shows that either the N-ras heterozygous null mutation (N-ras+/-) or a drug that decreases Ras function (FTI or farnesyl transferase inhibitor) can also reverse the learning deficits of the Nf1+/- mutants. These results suggest that increased Ras signaling is the cause for the learning deficits in Nf1+/- mutants.

After demonstrating that the Nf1+/- mutation affects hippocampal-dependent spatial learning, we searched for the hippocampal physiological deficits underlying the hippocampal-dependent learning abnormalities of Nf1+/- mutants. Our studies of Nf1+/- mice revealed clear deficits in long-term potentiation ( LTP; 50% reductions). LTP is a mechanism thought to be involved in learning and memory. Unlike LTP, other aspects of hippocampal physiology were unaffected by the Nf1+/- mutation (paired-pulse facilitation, augmentation, synaptic depression, recovery from synaptic depression, probability of release measured with the MK801 method, input resistance, single-cell firing thresholds, reversal of LTP, etc.). Our studies have also uncovered the possible cause for the LTP found that in Nf1+/- mutants: We discovered increased GABA-mediated inhibition in these mice. Remarkably, decreasing Ras function not only rescues the learning deficits of the Nf1+/- mutants, it also rescues their increase in GABA-inhibition and the decrease in LTP. Thus, our studies indicate that the Nf1 mutation leads to increased Ras function, that this leads to increased inhibition and that the increased inhibition results in the LTP deficits that probably underlie their learning impairments.