Insults to DNC in Mental Illness

Schizophrenia: Genetic Insults and Layer III of dlPFC

Many layer III dlPFC DNC proteins are genetically altered in schizophrenia, and/or have documented changes in expression. A number of proteins that normally serve to strengthen synaptic efficacy, e.g. by regulating Ca²⁺-cAMP signaling, are lost or weakened in schizophrenia, while those molecules that decrease PFC network connectivity by activating Ca²⁺-cAMP signaling are often increased in the dlPFC of patients with schizophrenia.

If you are interested: Arnsten AFT, Wang MJ, Paspalas CD (2012) Neuromodulation of thought: Flexibilities and vulnerabilities in prefrontal cortical network synapses. Neuron 76: 223-239.

Genetic Insults to Molecules that Inhibit the Stress Response

Many of the molecules that reign in the stress response are genetically altered in mental illness. For example, translocation in DISC1 is associated with a variety of mental illnesses including schizophrenia, depression and bipolar disorder; PDE4A is altered in schizophrenia, RGS4 is reduced in schizophrenia and bipolar disorder; and DGK has been associated with bipolar disorder where there may be excessive PKC signaling. The a2A-AR has been associated with ADHD. The loss of regulation of the stress response may contribute to PFC gray matter loss in these disorders.

If you are interested: Arnsten and Manji?(2008) Mania: A rational neurobiology. Future Neurology 3: 125-131. Arnsten (2011) Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. Int J Dev Neuro. 29: 215-23.

Relevance to Treatment

Most medications for mental illness target aspects of these pathways. For example, all atypical antipsychotics block NE a1-AR. All treatments for mania reduce PKC signaling, the discovery of the Manji lab (e.g. lithium, Depakote, carbemazepine, and high dose tamoxifen). Based in part on our research, the a1-AR antagonist, prazosin, is now in use for treating PTSD. And the a2A-AR agonist, guanfacine, is now in use for a variety of PFC disorders (see following links).

If you are interested:

Arnsten and Manji?(2008) Mania: A rational neurobiology. Future Neurology 3: 125-131.
Arnsten (2011) Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. Int J Dev Neuro. 29: 215-23.
Raskind et al (2013) A Trial of Prazosin for Combat Trauma PTSD With Nightmares in Active-Duty Soldiers Returned From Iraq and Afghanistan. Am J Psychiatry. Jul 12. [Epub ahead of print]