Genetic evidence for role of integration of fast and slow neurotransmission in schizophrenia.

The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ. Here, we review these findings from the standpoint of classical neurobiological knowledge of neuronal synaptic transmission and regulation of electrical excitability. We show that a substantial proportion of the identified genes are involved in intracellular cascades known to integrate 'slow' (G-protein-coupled receptors) and 'fast' (ionotropic receptors) neurotransmission converging on the protein DARPP-32. Inspection of the Human Brain Transcriptome Project database confirms that that these genes are indeed expressed in the brain, with the expression profile following specific developmental trajectories, underscoring their relevance to brain organization and function. These findings extend the existing pathophysiology hypothesis by suggesting a unifying role of dysregulation in neuronal excitability and synaptic integration in SCZ. This emergent model supports the concept of SCZ as an 'associative' disorder-a breakdown in the communication across different slow and fast neurotransmitter systems through intracellular signaling pathways-and may unify a number of currently competing hypotheses of SCZ pathophysiology.

Depth-resolved imaging of functional activation in the rat cerebral cortex using optical coherence tomography.

Co-registered optical coherence tomography (OCT) and video microscopy of the rat somatosensory cortex were acquired simultaneously through a thinned skull during forepaw electrical stimulation. Fractional signal change measured by OCT revealed a functional signal time course corresponding to the hemodynamic signal measurement made with video microscopy. OCT can provide high-resolution, cross-sectional images of functional neurovascular activation and may offer a new tool for basic neuroscience research in the important rat cerebral cortex model.

Analysis of LFP phase predicts sensory response of barrel cortex.

Several previous studies have shown the existence of Up and Down states and have linked their magnitude (e.g., depolarization level) to the size of sensory-evoked responses. Here, we studied how the temporal dynamics of such states influence the sensory-evoked response to vibrissa deflection. Under alpha-chloralose anesthesia, barrel cortex exhibits strong quasi-periodic approximately 1-Hz local field potential (LFP) oscillations generated by the synchronized fluctuation of large populations of neurons between depolarized (Up) and hyperpolarized (Down) states. Using a linear depth electrode array, we recorded the LFP and multiunit activity (MUA) simultaneously across multiple layers of the barrel column and used the LFP to approximate the subthreshold Up-Down fluctuations. Our central finding is that the MUA response is a strong function of the LFP oscillation's phase. When only ongoing LFP magnitude was considered, the response was largest in the Down state, in agreement with previous studies. However, consideration of the LFP phase revealed that the MUA response varied smoothly as a function of LFP phase in a manner that was not monotonically dependent on LFP magnitude. The LFP phase is therefore a better predictor of the MUA response than the LFP magnitude is. Our results suggest that, in the presence of ongoing oscillations, there can be a continuum of response properties and that each phase may, at times, need to be considered a distinct cortical state.

Spatial distribution and subunit composition of GABA(A) receptors in the inferior olivary nucleus.

GABAergic inhibitory feedback from the cerebellum onto the inferior olivary (IO) nucleus plays an important role in olivo-cerebellar function. In this study we characterized the physiology, subunit composition, and spatial distribution of gamma-aminobutyric acid-A (GABA(A)) receptors in the IO nucleus. Using brain stem slices, we identified two types of IO neuron response to local pressure application of GABA, depending on the site of application: a slow desensitizing response at the soma and a fast desensitizing response at the dendrites. The dendritic response had a more negative reversal potential than did the somatic response, which confirmed their spatial origin. Both responses showed voltage dependence characterized by an abrupt decrease in conductance at negative potentials. Interestingly, this change in conductance occurred in the range of potentials wherein subthreshold membrane potential oscillations usually occur in IO neurons. Immunostaining IO sections with antibodies for GABA(A) receptor subunits alpha 1, alpha 2, alpha 3, alpha 5, beta 2/3, and gamma 2 and against the postsynaptic anchoring protein gephyrin complemented the electrophysiological observation by showing a differential distribution of GABA(A) receptor subtypes in IO neurons. A receptor complex containing alpha 2 beta 2/3 gamma 2 subunits is clustered with gephyrin at presumptive synaptic sites, predominantly on distal dendrites. In addition, diffuse alpha 3, beta 2/3, and gamma 2 subunit staining on somata and in the neuropil presumably represents extrasynaptic receptors. Combining electrophysiology with immunocytochemistry, we concluded that alpha 2 beta 2/3 gamma 2 synaptic receptors generated the fast desensitizing (dendritic) response at synaptic sites whereas the slow desensitizing (somatic) response was generated by extrasynaptic alpha 3 beta 2/3 gamma 2 receptors.

Is the cerebellum like cerebellar-like structures?

The cerebellum and cerebellar-like structures (including the dorsal and medial octavolateral nucleus of fishes and amphibians, the electrosensory lateral line lobe of electroreceptive teleost fishes and the dorsal cochlear nucleus of mammals) have similar anatomy, common developmental origins and common cellular markers. Transplanted embryonic Purkinje cells integrate into cerebellar-like structures but not neighboring brain parenchyma, and mutations that cause cerebellar degeneration cause similar defects in cerebellar-like structures. This review advances the idea that these neuroanatomical and molecular similarities have functional equivalents. The main structural difference between the cerebellum and cerebellar-like structures, the inferior olivary nucleus, can be viewed as a relay station that evolution has interposed along the path of flow of primary sensory information to the cerebellum. Gating of sensory information to the cerebellum occurs at the level of inferior olivary nucleus depending on whether arriving information is expected. Activation of inferior olivary neurons leads to plasticity, and finely tuned inhibitory inputs suppress olivary excitation when the plasticity is not needed. Functionally, the olivo-cerebellar system performs the same kind of computation as cerebellar-like structures: the subtraction of sensory expectations.

To beat or not to beat: a decision taken at the network level.

The cells of the inferior olivary nucleus, the sole source of the cerebellar climbing fibers, form a network of electrically coupled neurons. Experimental observations show that these neurons produce a large repertoire of electrical signals, among which sub-threshold oscillations of the membrane potential. Simultaneous recordings from pairs of neurons and optical imaging of voltage sensitive dyes show that sub-threshold activity occurs in synchrony throughout the network. The mechanism underlying the generation of the sub-threshold oscillations is not fully understood. Experimental observations suggest that the electrical coupling is essential but insufficient for their generation. Several theoretical mechanisms have been suggested to explain these observations. Up-to-date, the most realistic model is the heterogeneity model, that assumes a certain degree of heterogeneity among olivary neurons. The heterogeneity model proposes that sub-threshold oscillations are produced by electrical coupling of neurons with the same types of ionic conductances, but with different densities. The variability in channel densities yield neurons of different functional types. The main prediction of the model is that different functional types of neurons should be found in the inferior olive. Dynamic clamp experiments support this prediction.