A recently published study in Journal of Neuroinflammation reports the finding that neurotensin (NT) is elevated in the serum of young children with autistic disorder [1]. In cultured rat cortical neurons, NT has been shown to increase glutamate outflow and to intensify N-methyl D-aspartic acid- (NMDA-) mediated glutamate signaling [2]. In addition, NT may enhance glutamate transmission and, in particular, activate NMDA receptors [3, 4]. Such overstimulation of NMDA glutamate receptors can lead to excitotoxicity [5]. Thus, factors that modulate glutamatergic transmission may affect glutamate-induced cell apoptosis.

Previous studies have suggested a possible role for a hyperglutaminergic state in autism [6]. Further, an antagonist of the NMDA glutamate receptor, memantine, has been shown to improve some symptoms in autism [7]. In contrast, there have been conflicting reports regarding the effects of NT on GABAergic synapses. At least one study has reported that NT inhibits GABAergic synaptic transmission in rats [8]. Other studies have indicated that NT enhances GABA release [9], activates GABAergic interneurons in rat prefrontal cortex [10], and increases GABAergic activity in rat hippocampus [11]. NT may act in the CNS as an atypical neuroleptic [12]. Studies using an antagonist of the NT receptor subtype 1 (NTS1) have elucidated the functions driven by this receptor [13], and antagonism of NTS1 has been suggested as a novel therapeutic approach for the treatment of Parkinson's disease [4].

The higher serum levels of NT in young patients with autistic disorder does not necessarily indicate a casual role in autism [1]. Elevated NT levels in autistic disorder could be a result of inflammation. However, considering the known imbalance in glutamate-to-GABA ratios in children with autism [14], the higher levels of glutamate in autism [14], the downregulation of GABA(A) receptors in autism [15], and the role of NT in excessive activation of the NMDA receptor and apoptosis [3, 4], NT may mediate brain damage in addition to activating inflammatory processes in autism. These observations collectively suggest a hypothesis that modulation of NT or of its receptors, in combination with traditional drugs, may provide a novel approach for the management of autism.