In JAMA Psychiatry, 25 January 2023:
# Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia
Recently completed genetic studies,1,2 the largest and most comprehensive of their kind, help resolve schizophrenia’s complex pathobiology. With a preponderance of implicated genes localizing to hippocampal glutamatergic neurons, in particular pathogenic loss-of-function mutations in subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) glutamate receptors, the genetics inform the disorder’s anatomy and its pathophysiology.
Functional and structural magnetic resonance imaging (MRI) anatomically concords with the genetics, localizing the hippocampus and its CA1 subdivision as the brain region affected first and foremost in schizophrenia.3 The pathophysiology of the disordered hippocampus emerges from functional imaging3,4 and magnetic resonance spectroscopy (MRS).5 Collectively, the disordered hippocampus is characterized by abnormal increases in glutamate levels, hyperactivity, and atrophy.6
Clinically, schizophrenia is characterized by both positive symptoms (ie, psychosis) and negative symptoms (ie, cognitive deficits). Support that the hippocampal pathophysiological state is linked to glutamate receptor loss of function on the one hand, and can drive schizophrenia’s symptoms on the other, is provided by medical conditions that phenocopy schizophrenia’s symptoms3: paraneoplastic limbic encephalitis caused by antibodies directed against either the hippocampal-enriched AMPA or NMDA receptors; neurotoxic syndromes induced by an overdose of drugs that inhibit the hippocampal-enriched NMDA receptors; and seizures that localize to and emanate from the hippocampus. Helping to mechanistically explain this clinical phenocopy and how it links to schizophrenia’s genetic triggers, inhibiting hippocampal glutamate receptors in mice causes hippocampal glutamate elevation, hyperactivity, and atrophy.7 Hippocampal hyperactivity can drive striatal dopamine release via monosynaptic connections with the striatum, explaining positive symptoms, and hippocampal atrophy can partly explain the disorder’s negative symptoms.7 An integration is now possible, connecting the disorder’s genetic triggers, to its pathophysiological state, through its defining symptoms (Figure).