Animal Models of Neurological Disease and of Cerebral Malformations

In the late 1970's and early 1980's the mutant mouse, Spastic, was studied to determine the origin of its neurological syndrome of tremors and abnormal righting behavior. An electrophysiological analysis suggested a deficit in inhibition at the level of the spinal cord, and treatment of normal mice with strychnine, which blocks glycinergic inhibition, caused these mice to mimic the behavior of the Spastic mice. Chemical studies then demonstrated that the Spastic mouse appears to have an absolute deficit in glycine receptors in the spinal cord and brainstem, despite normal receptor numbers for several other neurotransmitters. Thus, the work of White and Heller with this mutant was the first demonstration of a single-gene mutation causing a specific deficit in a central nervous system neurotransmitter receptor (Nature, 1982). It now appears likely that many neurological diseases without specific anatomic lesions reflect a similar pathophysiological mechanism.  Hereditary transmission of certain epilepsies in the human has been known for many years. The discovery and characterization of a mouse model with a single recessive mutant gene on chromosome 8 by Noebels and Sidman provided the opportunity to study an inherited epilepsy in this animal, which in adolescence exhibits absence and clonic seizures (clinically and electrographically) (Science, 1979). Spontaneous electrographic and clinical seizures of this type previously had only been recognized in humans. This work defined the first example of an inherited epilepsy model with a single recessive gene on an identified chromosome with clinical and EEG features similar to those in inherited human epilepsy.

Additionally, Sidman, Rakic and co-workers utilized mutant models of cerebral and cerebellar cortical development, e.g., "Reeler" and "Weaver" mice, to elucidate fundamental mechanisms of neuronal migration. This approach laid the groundwork for the explosion in the use of mutant mice in neuroscience and genetics to elucidate fundamental mechanisms of neuronal development and later to define the molecular genetics of neurogenetic disorders. Work with related animal models is very widespread in the current IDDRC (Kunkel, Corfas, Greenberg, Walsh and Pomeroy).