Associative Learning and Prefrontal Synaptic Plasticity Dysfunction in Schizophrenia

The altered glutamatergic and DA transmission proposed for schizophrenia may affect synaptic plasticity mechanisms in the PFC. A reduction of dendritic spines in PFC pyramidal neurons has been reported in schizophrenia brains (Glantz and Lewis, 2000) as well as in animals with a neonatal VH lesion (Lipska et al., 2001a), suggesting reduced excitatory synaptic inputs in this area. Decreases of N-acetyl aspartate (NAA) in schizophrenia (Bertolino et al., 1999) and in this animal model (Bertolino et al., 1997) also indicate that excitatory inputs to the PFC are reduced. Administration of NMDA antagonists such as MK-801 or phencyclidine (PCP) induces schizophrenia-like symptoms (Luby et al., 1959; Heresco- Levy and Javitt, 1998; Jentsch and Roth, 1999), These conditions would result in an impairment of LTP and LTD induction in the PFC. A number of factors known to modulate plasticity are affected both in schizophrenia and in animals with a neonatal VH lesion. For example, brain-derived neurotrophic factor (BDNF) is identified as an important regulator of synaptic plasticity (Balkowiec and Katz, 2002; Kovalchuk et al., 2002; Messaoudi et al., 2002). BDNF is affected in schizophrenia (Wassink et al., 1999; Krebs et al., 2000; Virgos et al., 2001) as well as in animals with a neonatal VH lesion, in which there is reduced expression of BDNF mRNA in the PFC (Lipska et al., 2001b; Ashe et al., 2002). Antipsychotics increase BDNF mRNA expression (Chlan-Fourney et al., 2002) and have been suggested to induce synaptic plasticity (Konradi and Heckers, 2001). In addition, BDNF modulates DA systems (Guillin et al., 2001). Thus, cortical synaptic plasticity may be altered in schizophrenia.

A synaptic plasticity deficit would in turn cause dysfunction of neural ensemble formation and alteration of neural transmission in the ventral

striatum (Fig. 6). Indeed, animals with a neonatal VH lesion also show altered responses to the VTA stimulation in the ventral striatum (Goto and O'Donnell, 2002). These abnormal responses are not observed when the PFC is lesioned (Goto and O'Donnell, 2003), suggesting that excessive glutamate release from the PFC in response to DA activation affects basal ganglia responses. The word “schizophrenia” as defined by Eugen Bleuler originates from the Greek words Schizein, “to split” and phren, “mind” (Bleuler, 1952). Thus, he identified the key symptom of schizophrenia as dissociative thinking. Its converse, associative learning, requires limbic-PFC interactions. Context-related information processed by the hippocampus must be incorporated into the cortico-basal ganglia networks to select the appropriate set of behavioral responses. Thus, deficits in limbic-PFC flow of information will disrupt goal-directed behaviors. Recent studies by Earl Miller have shown that the PFC indeed processes associative learning (Miller et al., 1996; Asaad et al., 1998; Miller, 2000; Miller and Cohen, 2001). There is also evidence that this is disrupted in schizophrenia (Gold et al., 2000; Martins Serra et al., 2001). Abnormal NMDA and DA activity resulting in impaired plasticity may be responsible for such cognitive

deficits in schizophrenia. Further studies in the role of synaptic plasticity in the PFC and its role in the formation of neural ensembles, which may mediate associative learning, can yield more insight for the central components responsible for schizophrenia pathophysiology.

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This work was supported by USPHS grants MH57683, MH60131, DA14020, and a NARSAD Independent Investigator Award to P. O’D.

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