Mitochondrial Dysfunction Leads to Cortical Under-Connectivity and Cognitive Impairment.

Under-connectivity between cerebral cortical association areas may underlie cognitive deficits in neurodevelopmental disorders, including the 22q11.2 deletion syndrome (22q11DS). Using the LgDel 22q11DS mouse model, we assessed cellular, molecular, and developmental origins of under-connectivity and its consequences for cognitive function.

Modeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development.

Understanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge.

Cognitive ability is associated with altered medial frontal cortical circuits in the LgDel mouse model of 22q11.2DS.

We established a relationship between cognitive deficits and cortical circuits in the LgDel model of 22q11 Deletion Syndrome (22q11DS)-a genetic syndrome with one of the most significant risks for schizophrenia and autism. In the LgDel mouse, optimal acquisition, execution, and reversal of a visually guided discrimination task, comparable to executive function tasks in primates including humans, are compromised; however, there is significant individual variation in degree of impairment. The task relies critically on the integrity of circuits in medial anterior frontal cortical regions.

Intact and impaired executive abilities in the BTBR mouse model of autism.

BTBR T+tf/J (BTBR) inbred mice are frequently used as a model of autism spectrum disorders (ASD) as they display social deficits and repetitive behaviors that resemble the symptoms of the human syndrome. Since deficits on tasks that measure cognitive (executive) control are also reliable phenotypes in ASD, we wanted to determine whether executive abilities were compromised in the mouse model. BTBR mice were trained on two visual discrimination paradigms requiring differing degrees of cognitive control.

Stimulus specific deficit on visual reversal learning after lesions of medial prefrontal cortex in the mouse.

Tests of executive abilities, such as discrimination reversal and attentional set shifting, are sensitive to prefrontal cortex (PFC) damage in primates. The purpose of the present study was to use a primate reversal task to determine if PFC in the mouse is involved in similar cognitive functions. Mice with lesions of medial PFC and Sham operated control animals were trained on a series of visual problems in a computer-automated touchscreen apparatus using stimuli that varied in either pattern (lines) or luminance (black-white).