Regrowing certain neural connections rebuilds working memories in mice.
Image: Gogos et al
One of the most prevalent and difficult-to-treat symptoms of schizophrenia isn't hearing voices or paranoia or any of the more popularly associated features of the disease—it's forgetting things. Memory deficits are associated with many if not most psychiatric disorders, but among schizophrenics, the problem is unique both in its severity and in its consistency among patients of all of the disease's highly distinct subtypes.
And like schizophrenia in general, memory problems are difficult to treat, to be generous. This may be about to change, however, as researchers from Columbia University and the New York State Psychiatric Institute have successfully, dramatically reversed memory deficits in mouse models by regrowing connections between neurons using a chemical compound. Their work is described today in the journal Neuron.
The intervention targets a genetic mutation known as the 22q11.2 microdeletion, which happens to be the single greatest genetic risk factor for the disease. While it's been observed in only about 1 to 2 percent of all schizophrenics, carrying the mutation increases the odds of developing schizophrenia 20- to 30-fold.
"Human carriers of the 22q11.2 microdeletion show a range of cognitive deficits, including working memory impairments, and ~30% of them develop schizophrenia," the authors note. Mice with an analogous mutation, "show impairments in spatial working memory, among other schizophrenia-related phenotypes. These impairments in working memory correlate with deficits in functional connectivity between the hippocampus and medial prefrontal cortex in the mutant animals." It's thought that the prefrontal cortex is responsible for implementing the brain's working memory, e.g. the short term memory operations that go into normal executive functioning.
The same group of researchers had already shown00332-3) that mice with the full mutation experience deficits in neural growth, particularly among the two aforementioned brain regions. Last year they showed that these deficits trace back specifically to the mutation-related overproduction of an enzyme called Gsk3β. This enzyme results in the underproduction of some proteins needed to build neural connections, e.g. axons. And with underdeveloped axons, patients wind up with a series of limitations on synaptic efficacy, which is more or less what it sounds like: the ability of some presynaptic input to influence a postsynaptic output or spike.
The brain should do this well, but Gsk3β winds up standing in the way.
The question has remained of how closely correlated the 22q11.2 microdeletion and its neural effects are to actual human behavior. Are they causally related? If so, then rebuilding these neural connections should begin to reverse the memory-limiting effects of the mutation and, with it, schizophrenia.
This is just what happened.
The researchers were able to limit Gsk3β thanks to a compound called SB-216763. Like a lot of drugs, this one works by binding itself to active sites on the targeted enzyme, rendering it ineffective. The compound was able to successfully rescue the normal connection-building processes in the mouse subjects, resulting in significant improvements to their working memory abilities. Their brains rebuilt themselves.
"[The results] elucidate a putative causal chain of events leading from the 22q11 microdeletion to its consequent effects on cognition, crossing multiple levels of analysis in the process," the current study concludes. "Finally, they provide a potential avenue for novel therapies aimed at enhancing cognition in 22q11.2 deletion carriers and perhaps a subset of patients with schizophrenia."
Schizophrenia's memory-related symptoms are pretty much untreatable at the moment. They represent a broader class of symptoms known as "negative symptoms," which are together the things that don't get much press: emotional flatness, lack of motivation, poor concentration. An oppressive, inescapable inertness.
Medication can help with the positive symptoms of schizophrenia a great deal, limiting things like delusions and hallucinations to basically nothing. But it's the negative symptoms that persist and it's through these that the disorder is able to persist as the brutal, disabling force that it is. Even if it only winds up applying to a subset of schizophrenics, any advance that hits these negative symptoms is a breakthrough.