2.17.1 Glutamate hypothesis of SZ
Glutamate is the most common neurotransmitter in the mammalian brain.
Glutamate receptors have excitatory properties and are important for neural development, neuronal survival and synaptic plasticity.
The glutamate receptors in the mammalian CNS are subdivided in:
Ionotropic recptors NMDA ligand gated ion channels AMPA
Kainate
Metabotropic mGluRs G-protein coupled
Table 6. Overview of the different Glutamate receptors
2.17.2 NMDA
Increasing evidence suggests that NMDA hypo-function is involved in the pathophysiology of SZ (Homayoun and Moghaddam, 2007). Low doses of NMDA antagonists like PCP, MK801 or Ketamine can induce SZ-like psychotic symptoms (Bian et al., 2009). PCP and Ketamine lead to decrease parvalbumin (PV) stained interneurons. Reduction of parvalbumin or somatostatin stained interneurons and decrease of mRNA expression of somatostatin, parvalbumin and glutamate acid decarboxylase (GAD 67) are key findings for SZ (Konradi et al., 2011). PCP and Ketamine lead to increased cortical glutamate level.
Elevated levels of glutamate are observed in some brain regions of SZ patients.
“At the Network level, psychomimetic doses of NMDA antagonist may favour the balance of excitation over inhibition by blocking NMDA-dependent excitatory inputs to GABAergic interneurons” (Christoph Ott, 2012 personal communication).
“Subcortical NMDA receptor dysfunction, leading to elevated cortical glutamate levels and potentially to excitotoxic processes, may be important, particularly in the early stages of the disease” (Christoph Ott, 2012 personal communication).
mGLu2/3
Recent findings suggest that the compound LY404039 and its oral prodrug LY2140023 targets the metabotropic glutamate system. The effective treatment of SZ patients is still under debate (Mezler et al., 2010).
2.17.3 Hyper- and hypo-frontality in SZ
The gamma frequency oscillations of SZ patients performing working-memory tasks are disturbed. Responsible for this is most likely loss of inhibition of parvalbumin positive (PV+) interneurons (Uhlhaas and Singer, 2010; Haenschel et al., 2009; Barr et al., 2010).
Figure 12: Prefrontal cortex, Thalamus and Hippocampus, connections in mice and man, modified by (Pratt et al., 2012).
Dysfunctional connectivity in schizophrenia. Aberrant activity in both rodent models of the disease (left panel) and in patients (right panel) is centred on prefrontal – hippocampal – thalamic networks.
2.17.4 From neuronal circuits to single synapses
A small functional substructure of the brain is a simple neuronal circuit. A neuronal circuit is defined as a hierarchical network of inhibitory and excitatory neurons. In the cerebral cortex excitatory glutamatergic pyramidal cells and inhibitory GABAergic neurons form a micro-network (Fig. 13). The pyramidal cells are specialised in the transfer of information between cortical areas and to other parts of the brain. The interneurons function as breaks and oscillation fine tuners to the pyramidal cells. Disturbance of the balance lead to circuit miss-function. In SZ a certain class of interneurons seem to be affected. The PV+
interneurons, including Basket cells and Chandelier cells, localised in the dorsolateral prefrontal cortex show a decrease in Glutamate decarboxylase isoform 67 kDa (GAD67) expression in SZ (Akbarian et al., 1995; Hashimoto et al., 2003; Marín, 2012). Expression of ERBB4 protein in humans and monkeys is restricted to the somatodendritic compartments of interneurons and is absent from pyramidal cells (Neddens et al., 2011; Neddens and Buonanno, 2011;
Buonanno, 2010). The precise localisation of ERBB4 in CNS has not been
Introduction
42 described systematically yet and has to be further analysed. For further information see: (Neddens and Buonanno, 2011).
Figure 13: Cortical interneuron network
Different classes of cortical interneurons are distinguished by morphology, neurochemical content, intrinsic electrophysiological properties and pattern of connectivity. Interneurons i.e.
Basket cells target the soma and basal dendrites of pyramidal cells, Chandelier cells contact the axon initial segment and Martinotti cells and neurogliaform cells primarily contact the dendrites of pyramidal cells. The cells form a complex network of inhibition and excitation synchronised to a distinct oscillation. Modified from (Marín, 2012).
2.17.5 Alterations found in the neuronal circuit
Two different reasons are hypothesised to be responsible for the reduced activity of the PV+ interneurons in SZ.
A loss of function of interneurons might be caused by (I) a reduction of inhibitory synapses number (Woo et al., 1998), or (II) by a failure in the recruitment of the interneurons to their correct final localisation, thereby preventing functional excitation of these inhibitory interneurons (Grunze et al., 1996; Gunduz-Bruce, 2009).
NMDA receptor antagonists or the conditional deletion of NR1 subunit of NMDAR lead to the dis-inhibition of excitatory pyramidal cells and a loss of synchrony, showing SZ like symptoms (Belforte et al., 2010; Carlén et al., 2012).
2.17.6 NRG1-ERBB4 in the development of PV+ interneurons
ERBB4 directs the migration of PV+ interneurons in response to NRG1 (Flames et al., 2004). NRG1-ERBB4 signalling controls the integration and synapse formation of PV+ interneurons with pyramidal cells in neuronal circuits (Fazzari et al., 2010). Moreover, PV+ interneurons deficient in ERBB4, receive less input by pyramidal cells than normal ones (Ting et al., 2011). Interestingly, mice lacking ERBB4 specific in PV+ Interneurons have an impaired working memory phenotype (Wen et al., 2010) resembling cognitive deficits observed in SZ.
An overview of the location and implication of the findings is given in (Fig. 14) for neuronal circuits and in (Fig. 15) for synapse.
Figure 14: Alterations found in cortical circuits SZ patients and animal models
Spines and 67kDa glutamate decarboxylase (Gad67) are reduced. Loss of ERBB4 alters presynaptic functions of the Chandelier cells and post synaptic the functions of the Basket cells, resulting in a loss of inhibitory function and synchrony. The Pyramidal cell responds with asynchronous hyperactivity.
Introduction
44
Figure 15 Synapse, modified (Pratt et al., 2012)
The picture shows the most prominent genes implicated in the aetiology of schizophrenia.
NRG1-ERBB4 signalling regulates the function and morphology of the synapse. DISC1 coordinates signalling pathways that regulate synaptic structure (DISC1 with phosphodiesterase 4B (PDE4B) and TRAF2 and NCK–interacting kinase (TNIK)) a7 subunit containing nicotinic acetylcholine receptors (nAChRs) are strongly implicated in disease risk via gene copy number variations. Major histocompatibility complex (MHC) molecules have some role in the maintenance and plasticity of synaptic connections. AMPA: (a-amino-3hydroxy-5methyl-4-isoxazole propionic acid receptor (AMPAR); mGluR: metabotropic glutamate receptor; NMDAR: N-methyl-D-aspartate receptor; PRSS16: serine protease 16;
VGLUT1: vesicular glutamate transporter 1.