Eric Kandel, of Columbia University and Nobel Laureate in Medicine, has turned his research attention to schizophrenia. His new research project (“Combining mouse models to analyze the polygenic nature of the cognitive symptoms of schizophrenia”) involves the generation of mouse models of the complex human disorder schizophrenia, particularly focusing on the cognitive deficits in working memory, which he believes, as do many other reductionistic researchers, reflects a core genetic vulnerability in schizophrenia, i.e., an endophenotype. For a good introduction to both the concept of phenotype and the use of mouse models in psychiatry see The endophenotype concept in psychiatry: etymology and strategic intentions” by Irving Gottesman and Todd Gould (2005) and “The genes and brains of mice and men” (apologies to John Steinbeck) by Laurence Tecott (2005), both published in Recent Advances in Genetics and Genomics: Implications for Psychiatry edited in 2005 by Nancy Andreasen for American Psychiatric Publishing. Kandel has addressed the molecular processes underlying the cognitive symptoms of schizophrenia, in particular, the molecular changes in the prefrontal cortex responsible for the defect in working memory (parenthetically, this is another example of the risks involved in assuming a reductionistic and mechanistic approach to the brain, to think of the deficits in working memory as tied to one neural region is premature and tunnel-visioned, for along with the metabolic reduction in the prefrontal areas are often metabolic increases in the limbic system and more posterior areas, e.g., hipppocampus and amygdala, suggesting downstream effects in which intensity of affects can downregulate prefrontal areas).

Kandel will address two major hypotheses in schizophrenia research: the dopamine (DA) hypothesis in which hyperactivity in mesolimbic/nigrostriatal DA systems may result in ‘positive’ symptoms (e.g., hallucinations and delusions) and hypoactivity in the mesocortical regions lead to ‘negative’ symptoms (alogia, anhedonia, anergia, abulia, etc.); and the glutamate (GLU) hypothesis in which the primary deficit is glutamatergic leading to secondary changes in the DA system.

Kandel will test various candidate genes that have been identified in patient populations: 1) COMT (Catecholomine-o-methyl-transferase), 2) the nicotinic a7 receptors, 3) Neuregulin-1 (NRG-a risk haplotype of this gene has been identified in two independent populations, Scottish and Icelandic). A reduction of erbB3, a neuregulin-1 receptor, has been observed in the prefrontal cortex of persons with schizophrenia and mice lacking one copy of the neuregulin-1 gene have a defect in pre-pulse inhibition (PPI), a cognitive function also observed in schizophrenia. In regard to the latter, in my book-in-progress, The Schizophrenias: Brain, Mind and Culture, I noted:

“In addition, the animals exposed early to maternal separation had reduced pre-pulse inhibition (PPI), an electrophysiological finding found to be reduced in schizophrenia. The PPI is an operational measure of sensorimotor gating, hypothesized to be related to deficient inhibitory filtering of information processing in these patients. Gouzoulis-Mayfrank (2002) also noted reductions in PPI in animals raised in social isolation, an effect which can be reversed by neuroleptics. These findings support the theory that early adverse neural events can result in permanent structural and functional abnormalities, increasing a vulnerability to psychiatric disorders, including the affective disorders and schizophrenia.”

Kandel notes that neuregulin is critical for neural development and may have a role in synaptic plasticity, in particular, regulating the NMDA receptor and thereby influencing glutamatergic neurotransmission. He will evaluate these mice cognitively, neurophysiologically and neuroanatomically to characterize any candidate schizophrenia-like defect. Kandel will then explore developmental processes by observing to what degree any defect persists after the gene is turned off. If so, he will evaluate the critical period of expression. Kandel hopes to explore polygenic models of schizophrenia in the mice. After analyzing the phenotype of the NRG mutant mice (a good name for an animated movie?-the NRG mutant mice), Kandel will cross them to one or more of the other models at his disposal to create a multigenic defect in the mouse. In each case, he will try to determine in these multigenic models whether there is a synergistic effect as determined either by an increase in working memory defects or the emergence of other defects that may be more associated with the positive symptoms. This would be a first attempt to evaluate the interaction between candidate genes in a mouse model of a complex polygenic psychiatric disorder.

One of my difficulties with this model, besides the obvious difficulties in centering on working memory deficits (I highly doubt that this is specific for schizophrenia? or is it like other endophenotypes, non-specific, observed in bipolar disorder, anxiety, depression, etc.) and using a mouse model for a complex human disorder, (patients arrive at the ER generally not complaining of working memory deficits, rather, persecutory voices, panic, suicidality, aggressive feelings, etc.) is that Kandel does not refer to the significant research base on the role of stress in prefrontal/working memory functions and/or the reversibility of this ‘defect’ through psychological interventions.

Again, I would like to quote passages from my volume-in-progress, The Schizophrenias: Brain, Mind and Culture:

“The word “schizophrenia” is derived from the Greek words “schizein,” meaning to split, and “phren” referring to mind (Bleuler), i.e., dissociative thinking. The converse of the latter is associative learning which requires, along with anxiety tolerance, limbic-prefrontal (PFC) interactions. Altered glutamatergic and dopaminergic neurotransmission in the PFC may affect synaptic plasticity. BDNF (brain derived neurotrophic factor) is an important regulator of synaptic plasticity. BDNF is depressed by stress and this depression is observed in persons with schizophrenia. BDNF also modulates DA (dopamine) systems. Cortical synaptic plasticity seems altered in schizophrenia. This is consistent with a view of schizophrenia, from a neuroscience perspective (if one were to broaden the perspective to the level of the whole person, then other phenomena, such as continuity and cohesiveness of the self, defensive processes, symbiotic deficits, etc, would need to be included), as significantly associated with profound anxiety and stress. Chronic stress significantly impairs limbic-prefrontal interaction. For a fuller elaboration of the above see Yukiori Goto et al (2004) “Dopamine modulation of prefrontal cortical neural ensembles and synaptic plasticity: Potential involvement in schizophrenia” in Prefrontal Cortex: From Synaptic Plasticity to Cognition edited by Satoru Otani for Kluwer Academic Publishers.

Kazushige Mizoguchi (2004), in the pharmacology department of Central Research Laboratories in Ibaraki, Japan, demonstrated that acute stress activates the mesoprefrontal dopaminergic system in rats, while chronic stress reduces dopaminergic neurotransmission (hypofrontality) in the PFC (prefrontal cortex). The latter results in working memory impairment through a D1 receptor involvement. Chronic stress induces a depressive behavioral state (negative symptoms in schizophrenia?), caused by a reduction in dopaminergic and serotonergic neurotransmission in the PFC. This research is detailed in Kazushige Mizoguchi (2004) “Stress and prefrontal cortical dysfunction in the rat,” in Prefrontal Cortex: From Synaptic Plasticity to Cognition edited by Satoru Otani for Kluwer Academic Publishers.

If one studies the neuroscience research on the effects of stress on neural structure and function from the perspectives of molecular biology, gene expression, etc as well as examines the neurocognitive, epidemiological, course and outcome literature, subjective accounts, the psychotherapy literature, etc, one could not neglect the glaring evidence that what we refer to as the schizophrenias are a heterogeneous group of disorders significantly associated with profound and chronic anxiety and stress.”

And as to the reversibility of working memory deficits:

“A team of investigators at the Institute of Psychiatry in London (Wykes et al 2002) demonstrated that patients with schizophrenia who had received a psychological treatment, cognitive remediation therapy (CRT), had significantly increased brain activation in regions associated with working memory, i.e., frontocortical areas.”

Addendum 060120

This new evidence fits with my model of the importance of stress/fear/anxiety in the neurochemistry/neurophysiology/neuroanatomy of the major psychiatric disorders, including bipolar and schizophrenic disorders. At the end of the article, it is noted that p11 is regulated by stress hormones (cortisol?). I have posted many times on the neurobiological connection between stress and depression. For a good volume demonstrating that chronic stress can psychobiologically lead to depression, see Stress, the Brain and Depression by Herman van Praag, Ron de Kloet & Jim van Os (2004) published by Cambridge University Press.

In addition, we are faced with the persistent problem of correlation vs. causation. Could stress and depression result in the alterations in p11 & 5HT (serotonin) rather than the other way around? And then setting up a non-linear relation between the two-a mutually reinforcing loop? There is good research evidence demonstrating that this can indeed be the case.

Also, there is the persistent problem of the relation between intracellular signal transduction and gene expression and the complex phenotype (and all of the involved neuromodulators, environmental, psychological and sociocultural modifying factors).

In regard to medications, we have to be careful of ex juvantibus logic (proposed by psychopharmacologist Giorgio Bignami), correcting levels of 5HT & the consequent improvement in depressive/stress symptoms does not necessarily prove that this is an etiological factor.

This is a short response due to the fact I have to catch a train. If there is interest, I can elaborate further on the issues involved with this research.

Brian Koehler PhD
New York University
80 East 11th Street #339
New York NY 10003
212.533.5687
brian_koehler@psychoanalysis.net