John Mastropaolo

Subtype diagnosis in schizophrenia and its relation to neuropsychological and computerized tomography measures

We compared schizophrenic patients with a subtype diagnosis of paranoia (n = 14) to those with nonparanoid subtype diagnoses (n = 18) on the Wisconsin Card Sorting Test (WCST) and multiple computed tomography (CT) scan measures. The results showed that patients with nonparanoid diagnoses sorted fewer categories and made more perseverative errors on the WCST than did patients with the paranoid diagnosis. However, patients in the nonparanoid group could not be distinguished from those in the paranoid group on CT scan measures of brain structure. Additionally, a significant correlation was found between right frontal sulcal enlargement on CT scans and the number of perseverative errors made on the WCST.

Sodium butyrate, an epigenetic interventional strategy, attenuates a stress-induced alteration of MK-801's pharmacologic action.

Twenty-four hours after mice are exposed to a single session of forced swimming in cold water, the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically precipitated seizures is reduced. Conceivably, this reduction in MK-801s antiseizure efficacy reflects a stress-induced alteration in NMDA receptor-mediated neurotransmission due to changes in gene expression 24 h after a single stress. Recently, epigenetic interventional strategies impacting expression of genes whose regulation is controlled by the acetylation status of histone proteins in the nucleosome, an octomeric complex of histone proteins and promoter regions of double-stranded DNA, have been tested in preclinical models of various neuropsychiatric disorders, including Huntington disease and major depression. These strategies have been studied extensively in cancer biology. In the current investigation, the severity of the stress-induced reduction of MK-801s ability to raise the threshold voltage for the elicitation of tonic hindlimb extension was reduced when sodium butyrate (1.5 g/kg, ip) was administered around the time of stress. Prior research showed that this dose of sodium butyrate reliably increased the acetylation status of H3 and H4 histone proteins in the hippocampus and cerebral cortex of mice. Thus, the attenuation of the stress-induced reduction of MK-801s antiseizure efficacy may be due to the increased acetylation of histone proteins in the nucleosomal core and promotion of gene expression. These data encourage development of epigenetic strategies to prevent some of the deleterious consequences of stress.

Animal Models of Psychosis

Although the thinking and affective and social disturbances of psychosis and schizophrenia may not be easily modeled, if at all, in infrahuman species, animal models can clarify genetic and developmental lesions leading to disruption of some of the key anatomical circuitry involved in their pathophysiology. Increasingly, it is appreciated that patients with schizophrenia manifest symptoms in a variety of discrete domains of psychopathology, including positive (e.g., hallucinations), negative (e.g., affective flattening and social withdrawal), cognitive (e.g., concretization of thought), mood (e.g., anhedonia), and motor (e.g., mannerisms and posturing) symptoms. These symptoms may reflect, in part, the spatially and temporally integrated outputs from these disrupted or faulty circuits. Major goals of current descriptive and pathological research in schizophrenia include the development of sensitive behavioral rating instruments for the assessment of the presence and severity of symptoms in discrete psychopathological domains, elucidation of unique neurotransmitter abnormalities that may underlie each of these discrete domains of psychopathology, and determining the quantitative contribution of each of these discrete domains of psychopathology to the functional disability manifested by patients with schizophrenia and other psychosis. Thus, animal models that reflect nondopaminergic neurotransmitter abnormalities implicated in the pathophysiology of these discrete domains of psychopathology are especially useful. In addition to clarifying aspects of the pathophysiology of these disorders, animal models are crucial for identifying candidate compounds that may be developed as medications; novel medications are especially needed for the negative and cognitive symptom domains of psychopathology, which may be less dependent on abnormalities of dopaminergic neurotransmission. The contributions of dopaminergic abnormalities to the pathophysiology of schizophrenia have been studied most intensively. The focus on dopaminergic abnormalities in schizophrenia was prompted by the complementary observations in humans that psychosis can be elicited by psychostimulant medications such as d-amphetamine, especially when they are abused, whereas the ability to inhibit competitively the binding of dopamine to the D2 type of dopamine receptor is a pharmacological property shared by all of the conventional antipsychotic medications. Psychostimulant medications are either indirect or directly acting dopamine agonists. These pharmacological observations in humans stimulated interest in the quantitative characterization of a variety of “hardwired” rodent behaviors elicited by dopamine agonists such as apomorphine and d-amphetamine; these behaviors include a variety of stereotypic behaviors (e.g., rearing, grooming, and sniffing), horizontal locomotion and “mouse climbing,” among other behaviors. These animal procedures have served as valuable screens for the identification of “dopamine blockers” and medications whose primary pharmacological actions involve modulation (dampening) of dopaminergic neurotransmission, which have proven especially effective in the attenuation of positive symptoms. However, the negative and cognitive symptom domains of psychopathology, which contribute very significantly to the functional disability of schizophrenia and other psychotic disorders, are not dramatically affected by these primarily dopaminergic interventions. Thus, there is also intense interest in animal models that mimic neurodevelopmental abnormalities and/or disruptions of neurotransmitter systems other than dopamine. The existence of neurodevelopmental abnormalities in at least some patients with schizophrenia, as reflected in subtle histopathological abnormalities in cortical lamination, the orientation and alignment of neurons within the hippocampus, and diminished cortical neuropil, has heightened interest in the adult developmental consequences of neonatal lesions of the hippocampus, which, thereby, deprive the developing frontal cortex of afferent inputs from the hippocampus, and genetic models associated with altered cortical lamination, such as the reeler mouse.

Interaction of cholinergic and glutamatergic transmission in the hippocampus: An in vitro autoradiographic receptor analysis

Quantitative in vitro receptor autoradiography was used to examine the effect of acute scopolamine administration on specific binding to components of the N-methyl-D-aspartate (NMDA) receptor complex in four regions of mouse hippocampus. The binding of [3H]glycine to the strychnine-insensitive site was increased 1 h after administration of scopolamine hydrobromide (10 mg/kg) in the ventral dentate gyrus. The study suggests that rapid alterations in strychnine-insensitive glycine binding can occur in response to cholinergic perturbations. Moreover, these data suggest a delicate interaction between cholinergic and glutamatergic projections in the hippocampus.

The Role of Excitatory Amino Acids and Intraneuronal Calcium in the Acute Intoxicational Effects of Ethanol

It is proposed that the acute intoxicational effects of ethanol result, in large part, from a diminished ability to elevate intraneuronal calcium ion concentrations via specific receptor-gated and voltage-gated mechanisms. Consistent with this hypothesis, there are compelling data showing that acute exposure to ethanol inhibits both NMDA-stimulated calcium ion uptake through its specific ionophore, and depolarization-dependent calcium ion uptake through the L-type voltage-sensitive channel

An epigenetic intervention interacts with genetic strain differences to modulate the stress-induced reduction of flurazepam's antiseizure efficacy in the mouse

Stress induces changes in the endogenous tone of both GABA and NMDA receptor-mediated neurotransmission in the intact mouse. Because changes are observed 24 h after stress, epigenetically-regulated alterations in gene expression may mediate these effects. In earlier work, sodium butyrate, a centrally-active histone deacetylase inhibitor that promotes gene expression, was shown to modulate the stress-induced reduction of the ability of MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist, to antagonize electrically-precipitated seizures. In the current study, we extended this work to look at sodium butyrates modulatory effect on stress-induced changes in the antiseizure efficacy of flurazepam, a benzodiazepine receptor agonist, in two strains of mice. Epigenetic mechanisms, genetic strain differences and a standard stress interacted to alter flurazepams antiseizure efficacy. These data support examination and development of epigenetic treatment strategies.

Schizophrenia Endophenotypes as Treatment Targets

The concept of the “endophenotype” will be reviewed and its potential to elucidate genetic variations that are causally related to schizophrenia and gene-environment interactions that may be obscured with dependence on the categorical diagnosis of this disorder or reliance on symptoms and symptom clusters to detect these associations. The identifi cation of endophenotypes that refl ect genetic variations may also lead to refi nement of diagnosis, especially subtyp-ing of the disorder. Conceivable, a spectrum of schizophrenias may exist refl ecting a cluster of critical endophenotypes that must be present in all individuals diagnosed with the disorder and/or discrete, nonover-lapping endophenotypes that are found in genetically-distinct groups of individuals; nonetheless, all patients that are diagnosed with the disorder using operationally-defi ned diagnostic criteria, such as DSM-IV-TR, share common phenotypic characteristics even though they may have different endophenotypic profi les. Moreover, because endophenotypes may refl ect pathophysiologi-cal processes that contribute to the emergence of the clinical syndrome, they may serve as “targets” for pharmacotherapeutic interventions that treat a fundamental pathophysiological disturbance, as opposed to “voices.” Also, because endophenotypes may be detected in unaffected relatives and patients with sub-syndromal disorder or spectrum disorder, these targeted interventions may prove benefi cial to the functionality of these persons as well (including prevention of emergence of the clinical syndrome); presumably, subtle defi cits in socialization and cognition in these seemingly unaffected or “less-affected” persons may be related to the genetic variations that will be elucidated by the endophenotypic approach. Finally, a heuristic example will be given of an evolving medication strategy that addresses a presumptive endophenotype of schizophrenia that is associated with a precise genetic locus on chromosome 15, whose region contains the promoter and gene for the α7 subunit of the nicotinic acetylcholine receptor. Because of the importance of the construct of the endophenotype to the elucidation of genetic variations and neurobiological mechanisms relevant to the clinical syndrome of schizophrenia, their segregation in seemingly unaffected family members and patients with schizophrenia spectrum disorders (e.g., schizotypy), utility in clarifying gene-environment interactions that can precipitate overt disorder, and potential role as targets for rationale pharmacotherapeutic strategies, the NIMH has funded a multi-site collaboration, i.e., the Consortium on the Genetics of Schizophrenia (COGS), whose goal is to examine “the genetic architecture of quantitative endo-phenotypes in families with schizophrenia.”1–3 Hopefully, the COGS will validate several “candidate” neurocognitive and neurophysiological endopheno-types, and clarify their potential to refi ne our diagnosis of the disorder and its subtypes, identify persons at-risk before overt expression of the disorder, clarify environmental and other “second-hit” risk factors that increase liability of expression of overt illness, and stimulate development of more effective pharmacotherapies.