Kaplan + Sadock's Synopsis of Psychiatry, 11e

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Chapter 1: Neural Sciences

define the GABAergic deficit in schizophrenia. It appears that the parvalbumin-positive GABAergic interneurons in the inter- mediate layers of the cortex bear the brunt of the pathology, which includes reduced expression of GAD67, parvalbumin, and the GABA transporter (GAT). The finding that GABA A receptors are upregulated, as measured by autoradiography or with antibodies, supports the theory that these changes reflect hypofunction of the presynaptic GABAergic neurons. These particular GABAergic interneurons, which include the chande- lier cells, play an important role in negative feedback inhibition to the pyramidal cells in the cortex. Despite this highly repro- ducible neuropathology, genes related to GABAergic function have not figured prominently in genomewide searches, suggest- ing that GABAergic deficits may be a downstream consequence of some more proximal genetic defects. The theory that hypofunction of NMDA receptors is an etiologic factor in schizophrenia initially arose from the observation that phen- cyclidine (PCP) and related dissociative anesthetics that block NMDA receptors produce a syndrome that can be indistinguishable from schizo- phrenia (Fig. 1.4-10). Dissociative anesthetics are so named because they prevent the acquisition of new memories while the patient is appar- ently conscious. In fact under laboratory conditions, low-dose infusion of ketamine can produce the positive symptoms, negative symptoms, and specific cognitive deficits associated with schizophrenia in clear consciousness. Subsequent studies indicated that low-dose ketamine can also cause enhanced amphetamine-induced subcortical dopamine release as is observed in schizophrenia as well as abnormal cortical event-related potentials (ERPs) and disruption of prepulse inhibition in experimental animals. A number of putative risk genes for schizophrenia are closely asso- ciated with NMDA receptor function. DAAO, which encodes a protein

that activates d-amino acid oxidase, has been repeatedly linked to the risk of schizophrenia. d-Amino acid oxidase itself has been associated with increased risk. Recently an allelic variant of serine racemase in the promoter region has also been associated with the risk for schizophre- nia. Each of these gene variants could reduce the availability of d-serine in the cortex, thereby impairing NMDA receptor function. Notably, cerebrospinal fluid (CSF) and blood levels of d-serine are significantly reduced in patients with schizophrenia. Neuregulin 1 appears to be a convincing risk gene and interacts directly with NMDA receptors. Dysbindin, another risk gene, is expressed in glutamatergic terminals. mGluR3, which downregulates glutamate release, has also been associ- ated with schizophrenia. Recent findings have provided a link between the GABAergic neuropathology and NMDA receptor hypofunction. Chronic treat- ment of rats with NMDA receptor antagonists causes a downregula- tion of GAD67, parvalbumin, and GAT. The sensitive subpopulation of GABAergic neurons is the rapidly firing interneurons that provide the perisomatic innervation of the pyramidal cells. Their NMDA receptors appear to be much more sensitive to antagonists than those less active GABAergic neurons and pyramidal cells. The subtly reduced GABAer- gic inhibition results in a disinhibition of the glutamatergic pyramidal output. This degradation of the inhibitory feedback could account for the cognitive deficits and negative symptoms in schizophrenia, and the disinhibited output also results in elevated subcortical dopamine release and psychosis. Thus psychosis would be considered a downstream event resulting from a disruption in critical glutamatergic–GABAergic synap- tic function in the cerebral cortex. Anxiety and Depression.  GABAergic dysfunction has been associated with anxiety disorders, especially panic disor- der, as well as with major depressive disorder. Clinically, there is considerable comorbidity between anxiety and affective dis- orders. Decreased levels of the GABA A receptor modulators, the three a -reduced neuroactive steroids, have been found both in plasma and in CSF in major depressive disorder. Effective treatment with selective serotonin reuptake inhibitors (SSRIs) increases the neurosteroid levels. In contrast, in patients with panic disorder, the plasma neurosteroid levels were significantly elevated, perhaps as a compensatory mechanism. Magnetic resonance spectroscopy (MRS) has disclosed significant reduc- tions in GABA levels in the anterior cingulate and in the basal ganglia of medicated patients with panic disorder. Positron emission tomography (PET) scanning reveals a highly selec- tive reduction in benzodiazepine receptor sites bilaterally in the insular cortex in panic disorder. A genomewide screen has shown significant linkage at 15q in a region containing GABA A receptor subunit genes and panic disorder. MRS reveals signifi- cant reductions in both GABA and glutamate/glutamine (Glx) in the prefrontal cortex in major depressive disorder. Postmor- tem studies indicate upregulation of the GABA A receptor a 1 and b 3 subunits in the cerebral cortices of depressed patients who committed suicide, consistent with a reduction in GABAergic neurotransmission. The reduced levels of GABA in the occipital cortex in episodes of major depressive disorder normalized with effective treatment with SSRI or with electroconvulsive therapy. Glutamatergic dysfunction has also been implicated in depression. NMDA receptor antagonists have antidepressant effects in several animal models of depression including forced swim, tail suspension, and learned helplessness. A single injec- tion of ketamine provides protection from the induction of behavioral despair in rats for up to 10 days. Chronic treatment with antidepressants alters the expression of NMDA receptor

−

GABA A

Pyramidal Cell

+

Parvalbumin + GABAergic Neuron

NMDAR

Ketamine Kynurenic Acid Low D-Serine

+

VTA Dopamine

Figure 1.4-10 Pathological circuit in schizophrenia. The NMDA receptors on the rapidly firing parvalbumin (PV) expressing GABAergic interneu- rons in the intermediate levels of the cortex are disproportionately sensitive to antagonists or loss of the coagonist, d -serine. NMDA receptor hypofunction causes reduced expression of PV, GAD67, and the GABA transporter and upregulation of GABA A receptors on pyramidal neurons. Disinhibition of the pyramidal neurons causes cognitive dysfunction and negative symptoms and drives excessive subcortical dopamine release resulting in psychosis. (From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry . 9 th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:83.)