PTEN: A master regulator of neuronal structure, function, and plasticity.

PTEN (phosphatase and tensin homolog on chromosome ten) is a dual protein/lipid phosphatase that dephosphorylates PIP3, thereby inhibiting the AKT/mTOR pathway. This inhibition ultimately decreases protein translation, cell proliferation and cell growth. In the central nervous system, inhibition of PTEN leads to increased stem cell proliferation, somatic, dendritic and axonal growth, accelerated spine maturation, diminished synaptic plasticity, and altered intrinsic excitability. In agreement with these findings, patients carrying single-copy inactivating mutations of PTEN suffer from autism, macrocephaly, mental retardation, and epilepsy.(1) (-) (9) Understanding the mechanisms through which PTEN modulates the structure, function, and plasticity of cortical networks is a major focus of study. Preventing and reversing the changes induced by loss of Pten in model animals will pave the way for treatments in humans

State-Dependent Subnetworks of Parvalbumin-Expressing Interneurons in Neocortex.

Brain state determines patterns of spiking output that underlie behavior. In neocortex, brain state is reflected in the spontaneous activity of the network, which is regulated in part by neuromodulatory input from the brain stem and by local inhibition. We find that fast-spiking, parvalbumin-expressing inhibitory neurons, which exert state-dependent control of network gain and spike patterns, cluster into two stable and functionally distinct subnetworks that are differentially engaged by ascending neuromodulation. One group is excited as a function of increased arousal state; this excitation is driven in part by the increase in cortical norepinephrine that occurs when the locus coeruleus is active. A second group is suppressed during movement when acetylcholine is released into the cortex via projections from the nucleus basalis. These data establish the presence of functionally independent subnetworks of Parvalbumin (PV) cells in the upper layers of the neocortex that are differentially engaged by the ascending reticular activating system

An inhibitory pull-push circuit in frontal cortex.

Push-pull is a canonical computation of excitatory cortical circuits. By contrast, we identify a pull-push inhibitory circuit in frontal cortex that originates in vasoactive intestinal polypeptide (VIP)-expressing interneurons. During arousal, VIP cells rapidly and directly inhibit pyramidal neurons; VIP cells also indirectly excite these pyramidal neurons via parallel disinhibition. Thus, arousal exerts a feedback pull-push influence on excitatory neurons-an inversion of the canonical push-pull of feedforward input

PTEN: A master regulator of neuronal structure, function, and plasticity.

PTEN (phosphatase and tensin homolog on chromosome ten) is a dual protein/lipid phosphatase that dephosphorylates PIP3, thereby inhibiting the AKT/mTOR pathway. This inhibition ultimately decreases protein translation, cell proliferation and cell growth. In the central nervous system, inhibition of PTEN leads to increased stem cell proliferation, somatic, dendritic and axonal growth, accelerated spine maturation, diminished synaptic plasticity, and altered intrinsic excitability. In agreement with these findings, patients carrying single-copy inactivating mutations of PTEN suffer from autism, macrocephaly, mental retardation, and epilepsy.(1) (-) (9) Understanding the mechanisms through which PTEN modulates the structure, function, and plasticity of cortical networks is a major focus of study. Preventing and reversing the changes induced by loss of Pten in model animals will pave the way for treatments in humans

State-Dependent Subnetworks of Parvalbumin-Expressing Interneurons in Neocortex.

Brain state determines patterns of spiking output that underlie behavior. In neocortex, brain state is reflected in the spontaneous activity of the network, which is regulated in part by neuromodulatory input from the brain stem and by local inhibition. We find that fast-spiking, parvalbumin-expressing inhibitory neurons, which exert state-dependent control of network gain and spike patterns, cluster into two stable and functionally distinct subnetworks that are differentially engaged by ascending neuromodulation. One group is excited as a function of increased arousal state; this excitation is driven in part by the increase in cortical norepinephrine that occurs when the locus coeruleus is active. A second group is suppressed during movement when acetylcholine is released into the cortex via projections from the nucleus basalis. These data establish the presence of functionally independent subnetworks of Parvalbumin (PV) cells in the upper layers of the neocortex that are differentially engaged by the ascending reticular activating system

PTEN

PTEN (phosphatase and tensin homolog on chromosome ten) is a dual protein/lipid phosphatase that dephosphorylates PIP3, thereby inhibiting the AKT/mTOR pathway. This inhibition ultimately decreases protein translation, cell proliferation and cell growth. In the central nervous system, inhibition of PTEN leads to increased stem cell proliferation, somatic, dendritic and axonal growth, accelerated spine maturation, diminished synaptic plasticity, and altered intrinsic excitability. In agreement with these findings, patients carrying single-copy inactivating mutations of PTEN suffer from autism, macrocephaly, mental retardation, and epilepsy.(1) (-) (9) Understanding the mechanisms through which PTEN modulates the structure, function, and plasticity of cortical networks is a major focus of study. Preventing and reversing the changes induced by loss of Pten in model animals will pave the way for treatments in humans

Overexpression of calcium-activated potassium channels underlies cortical dysfunction in a model of PTEN-associated autism

De novo phosphatase and tensin homolog on chromosome ten (PTEN) mutations are a cause of sporadic autism. How single-copy loss of PTEN alters neural function is not understood. Here we report that Pten haploinsufficiency increases the expression of small-conductance calcium-activated potassium channels. The resultant augmentation of this conductance increases the amplitude of the afterspike hyperpolarization, causing a decrease in intrinsic excitability. In vivo, this change in intrinsic excitability reduces evoked firing rates of cortical pyramidal neurons but does not alter receptive field tuning. The decreased in vivo firing rate is not associated with deficits in the dendritic integration of synaptic input or with changes in dendritic complexity. These findings identify calcium-activated potassium channelopathy as a cause of cortical dysfunction in the PTEN model of autism and provide potential molecular therapeutic targets