Saturday, April 20, 2024
4/20/2024
Schizophrenia (SCZ) affects about 1% of the world’s population and is characterized by symptoms that include hallucinations and delusions (positive symptoms); antisocial behavior and blunted emotions (negative symptoms); and deficits in working memory, executive function, and learning and memory (cognitive symptoms). Antipsychotics primarily acting through dopamine receptors (Drd2s) alleviate positive symptoms, some negative symptoms, and are mostly ineffective for cognitive symptoms. Thus, multiple neural circuits and mechanisms are implicated in SCZ symptom categories. Because the etiology of SCZ is unknown and valid SCZ mouse models are not available, we focus on 22q11.2 deletion syndrome (22q11DS), the most common microdeletion syndrome in humans, which increases the risk of SCZ 30 fold. Psychotic symptoms are clinically indistinguishable in patients with SCZ with or without 22q11DS and usually appear during late adolescence/early adulthood. Mouse models of 22q11DS (22q11DS mice) have been constructed and validated. Using these mice, we and others have identified cellular and molecular mechanisms underlying some cognitive and negative symptoms of 22q11DS. During the previous funding period, we also identified disrupted synaptic transmission in thalamocortical (TC) projections between the auditory thalamus and auditory cortex (ACx) in 22q11DS mice. Abnormal activity in these brain regions in humans is associated with auditory hallucinations. Disruption of TC projections occurs in mice at 3.5 months, which corresponds to late adolescence/early adulthood in humans, the age of positive symptom onset, and is rescued by antipsychotics and specific inhibitors of Drd2s. Our studies revealed that the TC deficit is caused by reduced glutamate release from thalamic afferents, resulting from the haploinsufficiency of the 22q11DS gene Dgcr8, which mediates microRNA (miR) biosynthesis. Dgcr8 haploinsufficiency leads to depletion of miR-338-3p, which in turn, elevates Drd2 levels in thalamic relay neurons. Elevated Drd2s decrease glutamate release in thalamic neurons. The expression of miR-338-3p is enriched in the thalamus and declines with age, which may underlie thalamus specificity and the mechanism of late onset of TC disruption. Although the TC mechanism appears to satisfy requirements for mediating positive symptoms, how it affects network activity in the ACx and auditory thalamus is unclear. In this competitive renewal application, we propose to analyze abnormal spontaneous activity in neuronal ensembles in the ACx and auditory thalamus in behaving mice. For the ACx, we will use 2-photon imaging through a cranial window, and for the auditory thalamus, we will use a head-attached miniscope (1-photon imaging) or 2-photon imaging through graded index lenses. We will also study the mechanisms underlying age-dependent decline in the expression of miR-338-3p and connect it to the late onset of abnormal synchronicity in the ACx of 22q11DS models. This work will elucidate new mechanisms of the most enigmatic symptoms of SCZ and provide a framework for the development of specific therapeutic interventions to alleviate positive symptoms in patients with this catastrophic disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
