Disclosure statement: Dr. Amy F.T. Arnsten and Yale University receive royalties from a license agreement with Shire Pharmaceuticals from the sales of IntunivTM (extended release guanfacine) for the treatment of Attention Deficit Hyperactivity Disorder and related disorders that involve prefrontal cortical dysfunction. Intuniv was approved by the FDA September 2009
The Arnsten Lab studies molecular influences on the higher cognitive functions of the prefrontal cortex (PFC), with the overarching goal of developing rational treatments for cognitive disorders in aging and mental illness. The lab uses a multi-disciplinary approach to understand mechanisms influencing working memory at the cellular and behavioral levels. Research has focused on how neuromodulators such as norepinephrine (NE) and dopamine (DA), dynamically modulate PFC cognitive function and physiology through intracellular signaling mechanisms. We have termed this rapid form of neuroplasticity Dynamic Network Connectivity (DNC). Our data explain how exposure to stress causes the rapid loss of PFC cognitive abilities, and how genetic mutations in molecules that regulate these pathways can lead to symptoms of mental illness. Dysregulation of these pathways also contributes to cognitive decline with normal aging. Understanding these mechanisms has led to successful new treatments for patients with PFC dysfunction, including medications for Attention Deficit Hyperactivity Disorder (ADHD), Post-Traumatic Stress Disorder (PTSD) and a potential treatment for schizophrenia and bipolar disorder.
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The prefrontal cortex (PFC) is the most evolved area of the primate brain, subserving our highest order cognitive abilities. The research of Patricia Goldman-Rakic showed that parallel sensory processing streams continue into the PFC, where they interact through extensive interconnections (drawing above by S. Mark Williams). Goldman-Rakic described the fundamental ability of the PFC to represent information that is no longer in the environment, and to use this “representational knowledge” to guide behavior, thought and affect. This representational knowledge is used to overcome distraction or prepotent responses, and to maintain goals in the face of interference.
Prefrontal Cortical Networks
Subserving Working Memory
Goldman-Rakic used a spatial working memory paradigm to uncover the neural basis of working memory abilities, and found that representational knowledge is encoded by networks of prefrontal cortical (PFC) pyramidal cells with shared stimulus properties, engaged in recurrent excitation (schematically illustrated in this drawing by Dr. S. Mark Williams, Pyramis Studios).These recurrent excitatory connections depend on glutamate actions at NMDA receptors. Spatial tuning is heightened through GABAergic, inhibitory connections between networks with dissimilar spatial properties (e.g. Rao et al, J. Neurosci 20: 485, 2000). The working memory abilities of the PFC are also highly dependent on the neuromodulatory environment, whereby loss of catecholamines in PFC is as detrimental as destruction of the PFC itself (Brozoski et al, Science 205: 929 1979).
Recent research from our lab has revealed that the physiological strength of PFC network connections can be dramatically altered in a dynamic manner (Arnsten, Paspalas, Gamo, Yang and Wang, Trends in Cognitive Sciences epub June 14, 2010). Molecular signaling events (e.g. cAMP) in the spines of PFC pyramidal dendrites can open or close ion channels near synaptic connections to rapidly and reversibly alter the strength of network inputs. This process can occur in a precise subset of spines to sculpt network inputs to a neuron, or more globally, e.g. to rapidly collapse network activity in response to an acute stressor. These actions can occur rapidly, in the timeframe of seconds, and thus allow great flexibility in cognitive ability. We have named this process Dynamic Network Connectivity (DNC).
DNC proteins such as HCN ion channels and cAMP signaling molecules appear to be concentrated in long, thin spines. Computational models indicate that this shape provides more effective shunting of synaptic connections (J. Pereira and X.J. Wang). This shape would also serve to sequester cAMP within the spine compartment to enhance specificity.
“DNC spines” are particularly evident in deep layer III, the sublayer subserving recurrent PFC microcircuits. This sublayer is also where the greatest spine loss is found in patients with schizophrenia (Glantz and Lewis, Arch Gen Psych 57:65-73, 2000). Thin spines are also lost from layer III with normal aging (Dumitriu et al, J Neurosci. 30:7507, 2010).
ImmunoEM micrographs of long, thin spines from layer III of dorsolateral PFC containing DNC proteins. HCN1= Hyperpolarization-activated Cyclic Nucleotide-gated channels; PDE4A = phosphodiesterase 4A, an enzyme that catabolizes cAMP. Images from Dr. C. Paspalas
Advantages of DNC:
- Provides negative feedback to prevent seizures in recurrent excitatory circuits
- Sculpts network inputs to a neuron, shunting nonpreferred inputs to reduce “noise” and sharpen tuning
- Flexibly adjusts PFC function based on available energy and the state of arousal, e.g strengthening PFC microcircuits in response to relevant events, but taking PFC “off-line” during fatigue or unconntrollable stress
Disadvantages of DNC:
- Negative feedback limits working memory capacity
- Highly vulnerable to environmental (e.g. chronic stress, aging) and genetic (e.g. schizophrenia) insults
Mechanisms that weaken network connectivity:
Opening of potassium channels weakens PFC connectivity and reduces neuronal firing. Calcium can diminish firing via opening of SK channels, while high levels of cAMP weaken network connectivity via opening of HCN and KCNQ channels. Stress exposure commandeers these pathways through high levels of catecholamine release. These weakening DNC mechanisms are shown in shades of red.
Mechanisms that strengthen network connectivity:
Molecules that inhibit calcium and/or cAMP signaling strengthen network connectivity, as do actions that open depolarizing channels (e.g. nicotinic α7 receptors). These enhancing mechanisms are shown in shades of green.
Optimal Levels of Dopamine D1
Sculpt Network Inputs:
Optimal levels of DA enhance spatial working memory by reducing PFC neuronal firing to nonpreferred inputs (see below). This sculpting effect arises from D1 receptor activation of cAMP signaling, leading to HCN and likely KCNQ channel opening and shunting of network inputs (Vijayraghavan et al, Nature Neurosci 10: 376, 2007). ImmunoEM suggests that D1 receptors and α2A adrenergic receptors reside on separate spines, but both co-localize with HCN channels. With high levels of D1 receptor activation, there is nonspecific suppression of all neuronal firing via cAMP signaling, perhaps arising from more widespread actions.
D1 Inverted U
The Arnsten Lab has shown that both DA and NE have “inverted U” influences on PFC cognitive functions. Thus, either too little or too much DA or NE impairs working memory at the cellular (shown) and behavioral levels. DA exhibits both beneficial and detrimental effects at D1/D5 receptors depending upon the amount of stimulation and the cognitive operation required, (Arnsten and Goldman-Rakic, 1990; Zahrt et al., 1997; Vijayraghavan et al, 2007). In contrast, NE has beneficial effects at post-synaptic ?2A receptors, and detrimental actions with high levels of ?1 receptor stimulation. This dissociation of receptor type with NE has allowed more expedient drug development for the treatment of PFC dysfunction.
Exposure to even quite mild uncontrollable stress impairs PFC cognitive functioning (reviewed in Arnsten, Science 280: 1711,1998, and Arnsten, Nature Rev. Neurosci 10: 410, 2009).This may have survival value when we are in danger, but is often detrimental in the Information Age when we depend on PFC functions to steer us through massive interference. It also leaves us vulnerable to mental illnesses such as depression and PTSD. The same signaling events that rapidly take PFC “off-line” (shown below), also strengthen the emotional and motor habits of the amygdala and striatum, thus switching us from a reflective to a reflexive state. Many of these signaling events appear to be synergistic, so that we rapidly switch from PFC to subcortical control, i.e. “Going to Hell in a Handbasket”. Medications that inhibit these pathways (guanfacine and prazosin) are now being tested in patients with PTSD, and may also help treat stress-related substance abuse.
Many of the molecular brakes on stress signaling pathways are genetically altered in mental illness, e.g. DISC1, RGS4 and DGK. For example, DAG kinase (DGK) has been linked to bipolar disorder and excessive PKC signaling, while treatments for bipolar disorder inhibit PKC signaling (reviewed in Arnsten and Manji, Future Neurology 3: 125, 2008). We have recently found that dendritic spine loss during chronic stress involves excessive PKC signaling, which may involve collapse of the actin cytoskeleton (Hains et al. PNAS 106: 17957, 2009). These data may explain why proper medication rescues PFC gray matter in patients with bipolar disorder (eg Blumberg et al Biol Psych 59:611, 2006).
Genetic Insults in Mental Illness
Genetic insults to intracellulara DNC signaling pathways in schizophrenia:
Many of the DNC molecules that strengthen PFC connectivity are genetically altered in patients with schizophrenia (shown in red; Arnsten et al, TICS, 2010). These genetic insults would weaken network connections- especially during stress exposure- and may contribute to spine loss.
Genetic Insults to extracellular DNC signaling pathways in ADHD:
ADHD is highly heritable, and some of these genetic insults involve changes in catecholamine transmission (shown in red). For example, a polymorphism in the promoter region of dopamine beta hydroxylase (dβh) leads to reduced NE synthesis and symptoms of PFC dysfunction (eg Kieling et al, 2008, Greene et al, 2009). Treatments for ADHD enhance catecholamine transmission by blocking NE transporters (NET), and/or DA transporters (DAT), or by mimicking NE at α2A receptors.
Guanfacine for the treatment of PFC disorders
Based on research from the Arnsten lab, an extended release formulation of the α2A adrenoceptor agonist, guanfacine (GFC), has been developed by Shire Pharmaceuticals for the treatment of ADHD (trade name of Intuniv). Guanfacine is also being tested in a number of additional disorders that involve weakened PFC function, including disinhibited behaviors in Tourette’s Syndrome (tic disorders), autism spectrum disorders, PTSD and drug addictions
Environmental insults to DNC with normal aging:
Many neuromodulators decline with advancing age (eg NE and ACh). There are also decreases in α2A receptors and in PDE4A which would disinhibit cAMP signaling (shown in red; Arnsten et al, TICS, 2010). Inhibition of cAMP-HCN channel signaling improves PFC function and physiology in aged animals. Normal aging is also associated with a substantial loss of DA from the aged PFC, which would diminish spatial tuning. However, D1 agonists have only limited beneficial effects in aged animals, perhaps because of dysregulation of cAMP signaling