PYRAMIDAL CELLS: ROLE IN PRIMATE PREFRONTAL CORTEX CIRCUITRY DURING POSTNATAL DEVELOPMENT AND SCHIZOPHRENIA

Cognitive deficits constitute a core feature of schizophrenia, are persistent across the course of the illness and are the best predictor of long-term functional outcome. Dysfunction in certain cognitive processes, such as working memory, are common in subjects with schizophrenia and have been attributed to aberrant function of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to reflect, at least in part, alterations in excitatory neurotransmission. Cortical pyramidal neurons, the principal source of cortical glutamate neurotransmission, exhibit highly robust molecular and morphological alterations in schizophrenia. These alterations appear to be most pronounced in DLPFC deep layer 3, the same microcircuit necessary for the generation of neural oscillations in the γ-frequency range that sustain working memory function. Understanding how dysfunction in DLPFC cortical circuits in deep layer 3 might give rise to the pathophysiology of altered γ-frequency oscillations and working memory deficits in schizophrenia require an interrogation of the mechanisms by which these neuropathological alterations may arise, but also the normal developmental trajectories of these vulnerable microcircuits. In this dissertation, we provide evidence for pyramidal cell type-specific molecular disturbances and synapse-specific structural impairments in DLPFC deep layer 3, and cell type-specific and layer-specific nature of postnatal developmental refinements in pyramidal cells in the DLPFC, within the circuitry that subserves γ-frequency oscillations and working memory. Accordingly, we have identified alterations in the expression of numerous molecular regulators of the actin cytoskeleton in a layer-specific and cell type-specific manner in DLPFC deep layer 3 in individuals with schizophrenia that might be a critical “upstream” cause in the pathogenesis of the illness. Additionally, using novel triple-label fluorescence immunohistochemistry and spinning-disk confocal microscopy, we characterize specific synaptic connections onto DLPFC deep layer 3 pyramidal cells in schizophrenia. Finally, we demonstrate that the developmental trajectories of primate DLPFC deep layer 3 pyramidal neurons are protracted, and layer-specific and posit that the molecular maturation of GABA synapses on pyramidal cells may account, at least in part, for the maturation of synchronized pyramidal cell firing which is crucial for γ-frequency oscillations

Loss of Prefrontal Cortical Higher Cognition with Uncontrollable Stress: Molecular Mechanisms, Changes with Age, and Relevance to Treatment

The newly evolved prefrontal cortex (PFC) generates goals for “top-down” control of behavior, thought, and emotion. However, these circuits are especially vulnerable to uncontrollable stress, with powerful, intracellular mechanisms that rapidly take the PFC “off-line.” High levels of norepinephrine and dopamine released during stress engage α1-AR and D1R, which activate feedforward calcium-cAMP signaling pathways that open nearby potassium channels to weaken connectivity and reduce PFC cell firing. Sustained weakening with chronic stress leads to atrophy of dendrites and spines. Understanding these signaling events helps to explain the increased susceptibility of the PFC to stress pathology during adolescence, when dopamine expression is increased in the PFC, and with advanced age, when the molecular “brakes” on stress signaling are diminished by loss of phosphodiesterases. These mechanisms have also led to pharmacological treatments for stress-related disorders, including guanfacine treatment of childhood trauma, and prazosin treatment of veterans and civilians with post-traumatic stress disorder

Synaptic actin dysregulation, a convergent mechanism of mental disorders?

Actin polymerization governs activity-dependent modulation of excitatory synapses, including their morphology and functionality. It is clear from human genetics that neuropsychiatric and neurodevelopmental disturbances are multigenetic in nature, highlighting the need to better understand the critical neural pathways associated with these disorders and how they are altered by genetic risk alleles. One such signaling pathway that is heavily implicated by candidate genes for psychiatric and neurodevelopmental disorders are regulators of signaling to the actin cytoskeleton, suggesting that its disruption and the ensuring abnormalities of spine structures and postsynaptic complexes is a commonly affected pathway in brain disorders. This review will discuss recent experimental findings that strongly support genetic evidence linking the synaptic cytoskeleton to mental disorders, such as schizophrenia and autism spectrum disorders. ©2016 the authors116161sciescopu