Serine racemase deletion disrupts memory for order and alters cortical dendritic morphology

Abstract

There is substantial evidence implicating N-methyl-d-aspartate receptors (NMDARs) in memory and cognition. It has also been suggested that NMDAR hypofunction might underlie the cognitive deficits observed in schizophrenia since morphological changes, including alterations in the dendritic architecture of pyramidal neurons in the prefrontal cortex (PFC), have been reported in the schizophrenic brain post mortem. Here, we used a genetic model of NMDAR hypofunction, a serine racemase knockout (SR−/−) mouse in which the first coding exon of the mouse serine racemase gene has been deleted, to explore the role of d-serine in regulating cognitive functions as well as dendritic architecture. SR −/− mice exhibited a significantly disrupted representation of the order of events in distinct experiences as revealed by object recognition and odor sequence tests; however, SR −/− animals were unimpaired in the detection of novel objects and in spatial displacement, and showed intact relational memory in a test of transitive inference. In addition, SR −/− mice exhibited normal sociability and preference for social novelty. Neurons in the medial PFC of SR−/− mice displayed reductions in the complexity, total length, and spine density of apical dendrites. These findings demonstrate that d-serine is important for specific aspects of cognition, as well as in regulating dendritic morphology of pyramidal neurons in the mPFC. Moreover, they suggest that NMDAR hypofunction might, in part, be responsible for the cognitive deficits and synaptic changes associated with schizophrenia, and highlight this signaling pathway as a potential target for therapeutic intervention.

Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction

“…3A) (P = 0.01). Accompanying the reduction in hippocampal volume, we also observed a significant reduction in spine (42,43). Consistent with these morphological abnormalities, the expression of miR-132, a known positive modulator of spine plasticity, was reduced.…”

“…Golgi staining was performed using the FD Rapid GolgiStain Kit (FD NeuroTechnologies) as previously described (42,43,78). Neurons were located between approximately −1.46 mm to −2.20 mm posterior to bregma (79) and within the middle third of the section.…”

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

“…Pharmacologic, post-mortem, and genetic findings provide convincing evidence that NMDA receptor hypofunction is a core feature of schizophrenia . The SRÀ/À mouse strain shares behavioral and neuropathological features with schizophrenia (Basu et al, 2009;Devito et al, 2010;. Given the inability of the SRÀ/À mice to extinguish AMPH-induced conditioned hyperactivity, perhaps the NMDA receptor hypofunction in schizophrenia contributes to the high prevalence of substance abuse by impairing their ability to remain abstinent (Coyle, 2006).…”

“…Furthermore, like conditioned hyperactivity, the extinction-induced reversal of spine density changes is dependent upon intact NMDA receptor signaling, as the SRÀ/À subject displays a failure to show extinction-related spine density reduction. This extinction-resistant spine plasticity in the NAc of the SRÀ/À subject builds on observations of reduced dendritic complexity and spine density in the cortex of both constitutive and conditional SR mutants to point a role for NMDA receptor signaling to the bidirectional regulation of dendritic spines in multiple brain regions (Devito et al, 2010;.…”

“…D-serine is synthesized through the racemization of its L-isomer by the enzyme serine racemase (SR). The understanding of the functional impact of GlyT1 and SR has been advanced by the use of recombinant mouse lines bearing knockout mutations to the genes encoding these proteins (Tsai et al, 2004;Martina et al, 2005;Basu et al, 2009;Devito et al, 2010;. The SR homozygous knockout (SRÀ/À) mutant and GlyT1 hypomorph (GlyT1À/ + ) represent functionally converse mutations that lead to either NMDA receptor hypofunction (SRÀ/À; Basu et al, 2009) or hyperfunction (GlyT1À/ + ; Martina et al, 2005).…”